Treatment of aneurysms with apolipoprotein c3 (APOC3) inhibitors and gene editing

Abstract

The present disclosure provides methods of treating subjects having aneurysms or at risk of developing aneurysms, preventing aneurysms, preventing the progression of aneurysms, or preventing a complication of an aneurysm by administering an Apolipoprotein C3 (APOC3) inhibitor to the subject or by gene editing methods.

Description

[0001] Treatment Of Aneurysms With Apolipoprotein C3 (APOC3) Inhibitors And Gene Editing

[0002] Field

[0003] The present disclosure generally relates to the prevention of aneurysms, prevention of the progression of aneurysms, treatment of subjects having aneurysms, or preventing a complication of an aneurysm by administering an apolipoprotein C3 (APOC3) inhibitor to the subject or by gene editing methods, and to methods of identifying subjects having an increased risk of developing aneurysms.

[0004] Background

[0005] An aneurysm is a weak or expanded portion of a blood vessel which can rupture and result in internal bleeding and possibly lead to death. Several types of aneurysms exist, the primary form being abdominal aortic aneurysm, and peripheral aneurysms, such as cerebral, thoracic aortic, carotid, popliteal, mesenteric, and splenic aneurysms. Aneurysm treatments include medication or surgery and although many aneurysms develop without causing symptoms, imaging tests can locate and help diagnose aneurysms.

[0006] The Apolipoprotein C3 (APOC3) gene encodes a protein component of triglyceride-rich chylomicrons, very low-density lipoproteins (VLDL), cholesterol remnants, and high-density lipoproteins (HDL). This gene and other related genes comprise an apolipoprotein gene cluster on chromosome 11. APOC3 is primarily expressed in the liver.

[0007] Cholesteryl Ester Transfer Protein (CETP) is a 22kb gene located at 16ql3. CETP is 493 amino acids long and is a 55 kDa protein that is involved in the transfer of neutral lipids, including cholesteryl ester and triglyceride, among lipoprotein particles. CETP allows the net movement of cholesteryl ester from high density lipoproteins / HDL to triglyceride-rich very low density lipoproteins / VLDL, and the equimolar transport of triglyceride from VLDL to HDL. CETP regulates the reverse cholesterol transport, by which excess cholesterol is removed from peripheral tissues and returned to the liver for elimination.

[0008] Proprotein convertase subtilisin / kexin type 9 is an enzyme (encoded by PCSK9) that binds LDLR and prevents recycling of LDLR to the cell surface. It has been observed that the addition of exogenous PCSK9 protein reduced LPS / LTA uptake into cells in vitro (Boyd, Inn. Immunol., 2016; Grin, Sci. Rep., 2018; and Leung, Sci. Rep., 2019). Lipoprotein(a) gene (LPA) is a 133 kb gene located at 6q25.3-q26. LPA encodes a serine proteinase that is 2040 amino acids long, 227 kDa, and inhibits the activity of tissue-type plasminogen activator I. The LPA gene is responsible for encoding apolipoprotein(a) (APOA), which is a component of lipoprotein(a). Thus, APOA is the protein produced by LPA gene. More specifically, Lp(a) is a particle composed of apolipoprotein B-100 (apoB-100) covalently bound to APOA, which is derived from kringle IV (KIV) and KV, and the protease domain of plasminogen. Lp(a) plasma concentrations are highly heritable and mainly controlled by the LPA gene. Large genetic epidemiological studies have documented strong, graded associations of high Lp(a) levels and corresponding LPA risk genotypes with increased risk of coronary heart disease (CHD) and calcific aortic valvular disease (CAVD). Other diseases associated with LPA include Lipoprotein Quantitative Trait Locus and Familial Hyperlipidemia.

[0009] Summary

[0010] The present disclosure provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, the methods comprising administering an APOC3 inhibitor to the subject.

[0011] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, by administering an aneurysm therapeutic agent or an aneurysm therapy, the methods comprising: determining or having determined whether the subject has an APOC3 variant nucleic acid molecule, by: obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising an APOC3 variant nucleic acid molecule; and administering or continuing to administer the aneurysm therapeutic agent in an amount that is the same as or less than a standard dosage amount or an aneurysm therapy, and / or an APOC3 inhibitor to a subject that is a APOC3 reference; administering or continuing to administer the aneurysm therapeutic agent in an amount that is the same as or less than a standard dosage amount or an aneurysm therapy, and / or an APOC3 inhibitor to a subject that is heterozygous for the APOC3 variant nucleic acid molecule; or administering or continuing to administer the aneurysm therapeutic agent in a standard dosage amount or an aneurysm therapy to a subject that is homozygous for the APOC3 variant nucleic acid molecule; wherein the presence of the APOC3 variant nucleic acid molecule indicates the subject has a decreased risk of developing an aneurysm.

[0012] The present disclosure also provides methods of identifying a subject having an increased risk of developing an aneurysm, the methods comprising: determining or having determined the presence or absence of an APOC3 variant nucleic acid molecule in a biological sample obtained from the subject; wherein: when the subject is APOC3 reference, then the subject has an increased risk of developing an aneurysm; and when the subject is heterozygous or homozygous for the APOC3 variant nucleic acid molecule, then the subject has a decreased risk of developing an aneurysm.

[0013] The present disclosure also provides aneurysm therapeutic agents for use in treating an aneurysm, preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm in a subject having an APOC3 variant nucleic acid molecule.

[0014] The present disclosure also provides APOC3 inhibitors for use in treating an aneurysm, preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm in a subject that is APOC3 reference or is heterozygous for an APOC3 variant nucleic acid molecule.

[0015] The present disclosure also provides methods of treating a subject having an abdominal aortic aneurysm or at risk of developing an abdominal aortic aneurysm, or preventing an abdominal aortic aneurysm, preventing progression of an abdominal aortic aneurysm, or preventing a complication of an abdominal aortic aneurysm, the methods comprising administering: a therapeutic agent that decreases LDL; and / or a therapeutic agent that increases HDL. In some embodiments, the therapeutic agent may decrease LDL and increase HDL at the same time. In some embodiments, the aforementioned therapeutic agent is an APOC3 inhibitor or a CETP inhibitor, or both.

[0016] The present disclosure also provides methods of treating a subject having an abdominal aortic aneurysm or at risk of developing an abdominal aortic aneurysm, or preventing an abdominal aortic aneurysm, preventing progression of an abdominal aortic aneurysm, or preventing a complication of an abdominal aortic aneurysm, the methods comprising administering a cholesteryl ester transfer protein (CETP) inhibitor to the subject.

[0017] The present disclosure also provides therapeutic agents that decrease LDL and / or therapeutic agents that increase HDL for use in treating an abdominal aortic aneurysm, preventing an abdominal aortic aneurysm, preventing progression of an abdominal aortic aneurysm, or preventing a complication of an abdominal aortic aneurysm in a subject. In some embodiments, the aforementioned therapeutic agent may decrease LDL and increase HDL at the same time. In some embodiments, the aforementioned therapeutic agent is an APOC3 inhibitor or a CETP inhibitor, or both.

[0018] The present disclosure also provides CETP inhibitors for use in treating an abdominal aortic aneurysm, preventing an abdominal aortic aneurysm, preventing progression of an abdominal aortic aneurysm, or preventing a complication of an abdominal aortic aneurysm in a subject.

[0019] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, the methods comprising performing gene editing on a subject that is APOC3 reference or heterozygous for an APOC3 variant nucleic acid molecule to replace the reference copy of the APOC3 gene with an APOC3 variant nucleic acid molecule.

[0020] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, the methods comprising performing gene editing on a subject that is PCSK9 reference or heterozygous for a PCSK9 variant nucleic acid molecule to replace the reference copy of the PCSK9 gene with a PCSK9 variant nucleic acid molecule.

[0021] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, the methods comprising performing gene editing on a subject that is heterozygous or homozygous for an LPA variant nucleic acid molecule to disrupt the LPA variant nucleic acid molecule.

[0022] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, by administering an aneurysm therapeutic agent or an aneurysm therapy, the methods comprising: determining or having determined whether the subject has an APOC3 variant nucleic acid molecule, by: obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising an APOC3 variant nucleic acid molecule; and performing or having performed gene editing on a subject that is APOC3 reference or heterozygous for the APOC3 variant nucleic acid molecule, to replace the reference copy of the APOC3 gene with an APOC3 variant nucleic acid molecule, wherein the lack of the APOC3 variant nucleic acid molecule in the subject indicates the subject has an increased risk of developing an aneurysm.

[0023] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, by administering an aneurysm therapeutic agent or an aneurysm therapy, the methods comprising: determining or having determined whether the subject has a PCSK9 variant nucleic acid molecule, by: obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising a PCSK9 variant nucleic acid molecule; and performing or having performed gene editing on a subject that is PCSK9 reference or heterozygous for the PCSK9 variant nucleic acid molecule, to replace the reference copy of the PCSK9 gene with a PCSK9 variant nucleic acid molecule, wherein the lack of the PCSK9 variant nucleic acid molecule in the subject indicates the subject has an increased risk of developing an aneurysm.

[0024] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, by administering an aneurysm therapeutic agent or an aneurysm therapy, the methods comprising: determining or having determined whether the subject has an LPA variant nucleic acid molecule, by: obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising an LPA variant nucleic acid molecule; and performing or having performed gene editing on a subject that is heterozygous or homozygous for the LPA variant nucleic acid molecule to disrupt the LPA variant nucleic acid molecule, wherein the presence of the LPA variant nucleic acid molecule in the subject indicates the subject has an increased risk of developing an aneurysm.

[0025] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, the methods comprising performing gene editing to disrupt the LPA gene in the subject, wherein the subject comprises an Lp(a) level > 31 mg / dL.

[0026] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, the method comprising: determining or having determined the level of Lp(a) in the subject by: obtaining or having obtained a biological sample from the subject; and performing or having performed an assay on the biological sample to determine if the subject has an Lp(a) level > 31 mg / dL; and performing or having performed gene editing on a subject that has an Lp(a) level > 31 mg / dL to disrupt the LPA gene in the subject; wherein an Lp(a) level > 31 mg / dL indicates the subject has an increased risk of developing an aneurysm.

[0027] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, the methods comprising performing gene editing to disrupt the LPA gene in the subject, wherein the subject comprises an LPA PRS that is greater than the 60% percentile.

[0028] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, the methods comprising: performing an LPA PRS for the subject; and performing gene editing to disrupt the LPA gene in the subject, wherein the subject comprises an LPA PRS that is greater than the 60% percentile; wherein an LPA PRS that is greater than the 60% percentile indicates the subject has an increased risk of developing an aneurysm.

[0029] The present disclosure also provides methods of treating a subject having an abdominal aortic aneurysm or at risk of developing an abdominal aortic aneurysm, or preventing an abdominal aortic aneurysm, preventing progression of an abdominal aortic aneurysm, or preventing a complication of an abdominal aortic aneurysm, the methods comprising administering: a PCSK9 inhibitor and an LPA inhibitor. Brief Description Of The Drawings

[0030] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0031] The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several features of the present disclosure.

[0032] Figure 1 (Panel A and Panel B) shows a new association with protection from abdominal aortic aneurysm that appear driven by the HDL-C raising effects of APOC3 mutations.

[0033] Figure 2 (Panel A and Panel B) shows common putative gain-of-function variant in CETP associated with higher abdominal aortic aneurysm risk.

[0034] Figure 3 shows effects of selected CETP inhibitors on lipids.

[0035] Figure 4 shows LDL-C and HDL-C associated variants influence abdominal aortic aneurysm risk.

[0036] Figure 5 shows that while HDL-C has minimal impact on coronary disease risk, it is an important etiological factor for abdominal aortic aneurysm; and that LDL-C is a causal risk factor for both abdominal aortic aneurysm and coronary artery disease.

[0037] Figure 6 shows APOC3 rare coding variants raise HDL-C and protect from abdominal aortic aneurysm.

[0038] Figure 7 shows PCSK9 rare coding variants associate with lower risk of abdominal aortic aneurysm.

[0039] Figure 8 shows analysis of ODYSSEY OUTCOMES trial showing 41% reduction in abdominal aortic aneurysm events with alirocumab, a PCSK9 inhibiting mAb.

[0040] Figure 9 shows higher Lp(a) levels or LPA genetic score associate with higher abdominal aortic aneurysm risk.

[0041] Figure 10 shows individuals who were carriers of both a low LPA genetic score and PCSK9 protective 46L allele were at lower risk of abdominal aortic aneurysms (AAA).

[0042] Description

[0043] Various terms relating to aspects of the present disclosure are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art, unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein.

[0044] Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is in no way intended that an order be inferred, in any respect. This holds for any possible non-expressed basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0045] As used herein, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise.

[0046] As used herein, the term "about" means that the recited numerical value is approximate and small variations would not significantly affect the practice of the disclosed embodiments. Where a numerical value is used, unless indicated otherwise by the context, the term "about" means the numerical value can vary by ±10% and remain within the scope of the disclosed embodiments.

[0047] As used herein, the term "comprising" may be replaced with "consisting" or "consisting essentially of" in particular embodiments as desired.

[0048] As used herein, the terms "nucleic acid", "nucleic acid molecule", "nucleic acid sequence", "polynucleotide", or "oligonucleotide" can comprise a polymeric form of nucleotides of any length, can comprise DNA and / or RNA, and can be single-stranded, doublestranded, or multiple stranded. One strand of a nucleic acid also refers to its complement.

[0049] As used herein, the term "subject" includes any animal, including mammals. Mammals include, but are not limited to, farm animals (such as, for example, horses, cows, and pigs), companion animals (such as, for example, dogs and cats), laboratory animals (such as, for example, mice, rats, and rabbits), and non-human primates. In some embodiments, the subject is a human. In some embodiments, the human is a patient under the care of a physician.

[0050] It has been observed in accordance with the present disclosure that rare APOC3 variant nucleic acid molecules (whether these variants are homozygous or heterozygous in a particular subject) associate with a decreased risk of developing aneurysms. It is believed that APOC3 variant nucleic acid molecules have not been associated with aneurysms in humans. Therefore, subjects that are APOC3 reference or heterozygous for an APOC3 variant nucleic acid molecule may be treated with an APOC3 inhibitor such that an aneurysm, or development thereof, is inhibited or prevented, progression of an aneurysm is inhibited or prevented, a complication of an aneurysm is inhibited or prevented, the symptoms of an aneurysm are reduced or prevented, and / or development of symptoms is repressed or prevented. In addition, subjects that are APOC3 reference or heterozygous for an APOC3 variant nucleic acid molecule, may be treated by gene editing to replace the reference copy of the APOC3 gene with an APOC3 variant nucleic acid molecule such that an aneurysm, or development thereof, is inhibited or prevented, progression of an aneurysm is inhibited or prevented, a complication of an aneurysm is inhibited or prevented, the symptoms of an aneurysm are reduced or prevented, and / or development of symptoms is repressed or prevented. It is also believed that such subjects having an aneurysm or at risk of developing an aneurysm may further be treated with one or more aneurysm therapeutic agents or an aneurysm therapy that treats or inhibits aneurysms. In addition, the present disclosure provides methods of leveraging the presence or absence of APOC3 variant nucleic acid molecules in subjects to identify or stratify risk is such subjects of developing aneurysms, or to diagnose subjects as having an increased risk of developing aneurysms.

[0051] It has also been observed in accordance with the present disclosure that rare PCSK9 variant nucleic acid molecules (whether these variants are homozygous or heterozygous in a particular subject) associate with a decreased risk of developing aneurysms. It has also been observed in accordance with the present disclosure that LPA variant nucleic acid molecules (whether these variants are homozygous or heterozygous in a particular subject), increased level of Lp(a) protein, and / or a polygenic risk score above a particular threshold associate with an increased risk of developing aneurysms. It is believed that PCSK9 and LPA variant nucleic acid molecules have not been associated with aneurysms in humans. Therefore, subjects that are PCSK9 reference or heterozygous for a PCSK9 variant nucleic acid molecule, or subjects that are heterozygous or homozygous for an LPA variant nucleic acid molecule may be treated by gene editing to replace the reference copy of the PCSK9 gene with a PCSK9 variant nucleic acid molecule, or to disrupt the LPA variant nucleic acid molecule such that an aneurysm, or development thereof, is inhibited or prevented, progression of an aneurysm is inhibited or prevented, a complication of an aneurysm is inhibited or prevented, the symptoms of an aneurysm are reduced or prevented, and / or development of symptoms is repressed or prevented. It is also believed that such subjects having an aneurysm or at risk of developing an aneurysm may further be treated with one or more aneurysm therapeutic agents that treat or inhibit aneurysms.

[0052] It has also been observed in accordance with the present disclosure that a genetic score predicted lipoprotein (a) levels was associated with AAA. Analysis of top tertile of LPA genetic score and PCSK9 R46L variant indicated an additive effect on AAA supportive of a combination therapy of lipoprotein (a) and PCSK9 inhibitors for treatment of AAA. Individuals who were carriers of both a low LPA genetic score and PCSK9 protective 46L allele were at lower risk of AAA with an odds ratio of 0.61, which was more pronounced than individuals with high LPA genetic risk and carriers of PCSK9 46L protective allele (odds ratio=0.77) and individuals with low LPA genetic risk and non-carriers of the PCSK9 46L protective allele (odds ratio=0.8).

[0053] For purpose of the present disclosure, throughout the application, wherein Lp(a) level is indicated, it's mg / dL value can be interpreted to the approximate equivalent of nmol / L value per the standard of Lp(a) conversion table, subject to the specific assay. For example, 31 mg / dL is perceived as roughly equivalent to 75 nmol / L.

[0054] For purposes of the present disclosure, any particular subject, such as a human, can be categorized as having one of three APOC3 genotypes: i) APOC3 reference; ii) heterozygous for an APOC3 variant nucleic acid molecule; or iii) homozygous for an APOC3 variant nucleic acid molecule. A subject is APOC3 reference when the subject does not have a copy of an APOC3 variant nucleic acid molecule. A subject is heterozygous for an APOC3 variant nucleic acid molecule when the subject has a single copy of an APOC3 variant nucleic acid molecule. A subject is homozygous for an APOC3 variant nucleic acid molecule when the subject has two copies of an APOC3 variant nucleic acid molecule.

[0055] For purposes of the present disclosure, any particular subject, such as a human, can be categorized as having one of three PCSK9 genotypes: i) PCSK9 reference; ii) heterozygous for a PCSK9 variant nucleic acid molecule; or iii) homozygous for a PCSK9 variant nucleic acid molecule. A subject is PCSK9 reference when the subject does not have a copy of a PCSK9 variant nucleic acid molecule. A subject is heterozygous for a PCSK9 variant nucleic acid molecule when the subject has a single copy of a PCSK9 variant nucleic acid molecule. A subject is homozygous for a PCSK9 variant nucleic acid molecule when the subject has two copies of a PCSK9 variant nucleic acid molecule. For purposes of the present disclosure, any particular subject, such as a human, can be categorized as having one of three LPA genotypes: i) LPA reference; ii) heterozygous for an LPA variant nucleic acid molecule; or iii) homozygous for an LPA variant nucleic acid molecule. A subject is LPA reference when the subject does not have a copy of an LPA variant nucleic acid molecule. A subject is heterozygous for an LPA variant nucleic acid molecule when the subject has a single copy of an LPA variant nucleic acid molecule. A subject is homozygous for an LPA variant nucleic acid molecule when the subject has two copies of an LPA variant nucleic acid molecule.

[0056] In any of the embodiments described herein, the APOC3 variant nucleic acid molecule can be any nucleic acid molecule (such as, a genomic nucleic acid molecule, an mRNA molecule, or a cDNA molecule produced from an mRNA molecule) encoding an APOC3 variant polypeptide having a partial loss-of-function, a complete I oss-of-f unction, a predicted partial loss-of-function, or a predicted complete loss-of-function. A subject who has an APOC3 polypeptide having a partial loss-of-function (or predicted partial loss-of-function) is hypomorphic for APOC3. In some embodiments, the APOC3 variant nucleic acid molecule results in decreased or aberrant expression or activity of APOC3 mRNA or polypeptide. In some embodiments, the APOC3 variant nucleic acid molecule is associated with a reduced in vitro response to APOC3 ligands compared with reference APOC3. In some embodiments, the APOC3 variant nucleic acid molecule is a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, an in-frame indel variant, or a variant that encodes a truncated APOC3 variant polypeptide. In some embodiments, the APOC3 variant nucleic acid molecule is a missense variant nucleic acid molecule. In some embodiments, the APOC3 variant nucleic acid molecule comprises a single nucleotide polymorphism (SNP). In some embodiments, the APOC3 variant nucleic acid molecule comprises a variation in a coding region. In some embodiments, the APOC3 variant nucleic acid molecule does not comprise a variation in a non-coding region, except for a splice acceptor region (two bases before the start of any exon except the first). In some embodiments, the APOC3 variant nucleic acid molecule results or is predicted to result in a premature truncation of an APOC3 polypeptide compared to the reference APOC3. In some embodiments, the APOC3 variant nucleic acid molecule is a variant that is predicted to be damaging to the protein function (and hence, in this case, protective to the human) by in vitro prediction algorithms such as Polyphen, SIFT, or similar algorithms. In some embodiments, the APOC3 variant nucleic acid molecule is a variant that causes or is predicted to cause a nonsynonymous amino acid substitution in an APOC3 nucleic acid molecule and whose allele frequency is less than 1 / 100 alleles in the population from which the subject is selected. In some embodiments, the APOC3 variant nucleic acid molecule is any rare missense variant (allele frequency < 0.1%; or 1 in 1,000 alleles), or any splice-site, stopgain, start-loss, stop-loss, frameshift, or in-frame indel, or other frameshift APOC3 variant.

[0057] In any of the embodiments described herein, the APOC3 variant genomic nucleic acid molecule may include one or more variations at any of the positions of chromosome 11 (i.e., positions 116829907-116833072) using the nucleotide sequence of the APOC3 reference genomic nucleic acid molecule in the GRCh38 / hg38 human genome assembly (see, ENSG00000110245.12, ENST00000227667.8 annotated in the in the Ensembl database (URL: world wide web at "uswest.ensembl.org / Homo_sapiens / Gene / )) as a reference sequence. The sequences provided in these transcripts for the APOC3 genomic nucleic acid molecule are only exemplary sequences. Other sequences for the APOC3 genomic nucleic acid molecule are also possible.

[0058] In any of the embodiments described herein, the APOC3 variant nucleic acid molecule may comprise any one or more of the following genetic variations in the genomic nucleic acid molecule (referring to the chromosome:positions set forth in the GRCh38 / hg38 human genome assembly) listed in Table 1. In any of the embodiments described herein, the APOC3 variant nucleic acid molecule may comprise any one or more of the following genetic variations in the genomic nucleic acid molecule (referring to the chromosome:positions set forth in the GRCh38 / hg38 human genome assembly): ll:116830491:A:T, ll:116830530:T:C, ll:116830568:A:G, ll:116830616:C:CT, ll:116830637:C:T, ll:116830638:G:A, ll:116830897:G:T, 11:116832769:G:A, ll:116832770:G:A, 11:116832882:T:G, ll:116830535:AC:A, ll:116830897:G:A, ll:116830898:T:A, 11:116832768:TG:T, 11:116832882:T:A, ll:116830491:A:C, ll:116830531:G:T, ll:116830542:GT:G, ll:116830584:T:C, ll:116830584:T:G, ll:116830638:G:T, ll:116830771:A:G, ll:116830868:C:T, ll:116830886:C:T, ll:116832805:G:A, 11:116832879:GCCTGAGA:G, ll:116830772:G:T, and 11:116832799:AC:A, or an mRNA molecule produced therefrom, or a cDNA molecule produced from the mRNA molecule. In some embodiments, the subject being treated is heterozygous for the APOC3 variant nucleic acid molecule. In some embodiments, the subject being treated is APOC3 reference.

[0059] Table 1: Predicted loss of function variants in APOC3 identified by whole exome sequencing

[0060] For subjects that are genotyped or determined to be APOC3 reference, such subjects have an increased risk of developing aneurysms. For subjects that are genotyped or determined to be either APOC3 reference or heterozygous for an APOC3 variant nucleic acid molecule, such subjects can be treated with an APOC3 inhibitor.

[0061] For subjects that are genotyped or determined to be APOC3 reference or only heterozygous for an APOC3 variant nucleic acid molecule, such subjects have an increased risk of developing aneurysms and are candidates for gene editing in which the one or two copies of the APOC3 reference gene are replaced with a copy of an APOC3 variant nucleic acid molecule. In any of the embodiments described herein, the PCSK9 variant nucleic acid molecule can be any nucleic acid molecule (such as, a genomic nucleic acid molecule, an mRNA molecule, or a cDNA molecule produced from an mRNA molecule) encoding a PCSK9 variant polypeptide having a partial loss-of -function, a complete loss-of-function, a predicted partial loss-of- function, or a predicted complete loss-of-function. A subject who has a PCSK9 polypeptide having a partial loss-of-function (or predicted partial loss-of-function) is hypomorphic for PCSK9. In some embodiments, the PCSK9 variant nucleic acid molecule results in decreased or aberrant expression or activity of PCSK9 mRNA or polypeptide. In some embodiments, the PCSK9 variant nucleic acid molecule is associated with a reduced in vitro response to PCSK9 ligands compared with reference PCSK9. In some embodiments, the PCSK9 variant nucleic acid molecule is a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, an in-frame indel variant, or a variant that encodes a truncated PCSK9 variant polypeptide. In some embodiments, the PCSK9 variant nucleic acid molecule is a missense variant nucleic acid molecule. In some embodiments, the PCSK9 variant nucleic acid molecule comprises a single nucleotide polymorphism (SNP). In some embodiments, the PCSK9 variant nucleic acid molecule comprises a variation in a coding region. In some embodiments, the PCSK9 variant nucleic acid molecule does not comprise a variation in a non-coding region, except for a splice acceptor region (two bases before the start of any exon except the first). In some embodiments, the PCSK9 variant nucleic acid molecule results or is predicted to result in a premature truncation of a PCSK9 polypeptide compared to the reference PCSK9. In some embodiments, the PCSK9 variant nucleic acid molecule is a variant that is predicted to be damaging to the protein function (and hence, in this case, protective to the human) by in vitro prediction algorithms such as Polyphen, SIFT, or similar algorithms. In some embodiments, the PCSK9 variant nucleic acid molecule is a variant that causes or is predicted to cause a nonsynonymous amino acid substitution in a PCSK9 nucleic acid molecule and whose allele frequency is less than 1 / 100 alleles in the population from which the subject is selected. In some embodiments, the PCSK9 variant nucleic acid molecule is any rare missense variant (allele frequency < 0.1%; or 1 in 1,000 alleles), or any splice-site, stop-gain, start-loss, stop-loss, frameshift, or in-frame indel, or other frameshift PCSK9 variant.

[0062] In any of the embodiments described herein, the PCSK9 variant genomic nucleic acid molecule may include one or more variations at any of the positions of chromosome 1 (i.e., positions 55,039,447 to 55,064,852) using the nucleotide sequence of the PCSK9 reference genomic nucleic acid molecule in the GRCh38 / hg38 human genome assembly (see, ENSG00000169174.12, ENST00000302118.5 annotated in the in the Ensembl database (URL: world wide web at "https: / / useast.ensembl.org / Homo_sapiens / Gene / Summary? g=ENSG00000169174;r=l:55039447-55064852;transcript=ENST00000302118.5")) as a reference sequence. The sequences provided in these transcripts for the PCSK9 genomic nucleic acid molecule are only exemplary sequences. Other sequences for the PCSK9 genomic nucleic acid molecule are also possible.

[0063] In any of the embodiments described herein, the PCSK9 variant nucleic acid molecule may comprise any one or more of the following genetic variations in the genomic nucleic acid molecule (referring to the chromosome:positions set forth in the GRCh38 / hg38 human genome assembly): l:55039839:T:A, l:55039895:C:G, l:55039916:G:T, l:55039952:G:A, l:55039971:T:C, l:55039973:C:T, l:55039977:C:G, l:55039979:G:A, l:55039997:GA:G, l:55040000:GCACCC:G, l:55040034:G:T, l:55043847:C:T, l:55043857:G:T, l:55043870:G:A, l:55043871:T:C, l:55043873:G:T, l:55043901:C:G, l:55043912:C:T, l:55043922:G:A, l:55043924:C:T, l:55043925:G:A, l:55043933:G:A, l:55043945:C:T, l:55043946:G:A, l:55043948:C:T, l:55043972:C:T, l:55043996:G:A, l:55044010:G:C, l:55044017:G:A, l:55044020:G:A, l:55044035:G:A, l:55046524:C:A, l:55046544:G:A, l:55046553:G:A, l:55046587:C:T, l:55046601:C:T, l:55046602:G:A, l:55046610:C:A, l:55046640:C:T, l:55046644:C:T, l:55046647:G:A, l:55052295:G:C, l:55052307:C:G, l:55052371:A:G, l:55052380:C:A, l:55052382:G:A, l:55052391:G:A, l:55052409:C:G, l:55052651:C:A, l:55052666:G:C, l:55052677:C:T, l:55052697:C:A, l:55052698:G:A, l:55052701:C:T, l:55052713:G:A, l:55052734:C:T, l:55052735:G:A, l:55052753:A:T, l:55052771:C:T, l:55052791:G:A, l:55055999:A:T, l:55056019:C:A, l:55056040:C:A, l:55056056:C:T, l:55056085:A:G, l:55056151:G:A, l:55056154:G:A, l:55057329:A:G, l:55057340:G:A, l:55057374:C:T, l:55057403:C:T, l:55057407:G:A, l:55057410:T:G, l:55057433:G:C, l:55057436:A:G, l:55057454:G:A, l:55057464:C:T, l:55057468:C:G, l:55057475:T:C, 1:55057475 :TCA:T, l:55057508:G:A, l:55057514:G:A, l:55058066:C:T, l:55058096:G:T, l:55058156:G:A, l:55058188:C:T, l:55058191:C:A, l:55058197:A:ACC, l:55058498:G:T, l:55058516:A:G, l:55058538:C:T, l:55058543:C:G, 1:55058549 :C:T, l:55058570:C:T, l:55058580:C:T, l:55058617:GA:G, l:55058627:C:T, l:55058630:C:T, l:55058631:G:A, l:55058636:G:T, l:55059489:C:T, l:55059496:G:A, l:55059537:G:A, l:55059538:G:A, l:55059544:A:G, l:55059546:G:A, l:55059586:G:A, l:55059627:C:T, l:55059660:A:G, l:55061485:G:A, l:55061498:A:G, l:55063370:T:G, l:55063460:A:G, l:55063474:A:G, l:55063480:C:T, l:55063485:CG:C, l:55063486:G:A, l:55063487:TCAGCA:T, l:55063543:C:T, l:55063544:G:A, l:55063561:C:T, l:55063582:T:C, l:55039842:G:A, l:55039857:G:T, l:55039926:C:A, l:55039940:G:T, l:55039973:C:T, l:55039979:G:A, l:55039982:G:A, l:55040034:G:A, l:55043847:C:T, l:55043870:G:A, l:55043871:T:C, l:55043901:C:G, l:55043907:C:G, l:55043909:G:A, l:55043912:C:A, l:55043912:C:T, l:55043924:C:T, l:55043925:G:A, l:55043930:C:A, l:55043933:G:A, l:55043945:C:T, l:55043946:G:A, l:55043966:A:T, l:55043973:A:G, l:55043999:T:G, l:55044010:G:C, l:55044017:G:A, l:55046553:G:A, l:55046581:G:A, l:55046585:C:G, l:55046587:C:T, l:55046601:C:T, l:55046602:G:A, l:55046610:C:G, l:55046640:C:G, l:55046646:G:A, l:55046647:G:A, l:55052276:A:G, l:55052307:C:G, l:55052333:C:A, l:55052343:G:A, l:55052370:G:A, l:55052380:C:A, l:55052382:G:A, l:55052397:C:T, l:55052401:T:C, l:55052409:C:G, l:55052698:G:A, l:55052701:C:T, l:55052702:G:A, l:55052707:G:C, l:55052711:G:C, l:55052734:C:T, l:55052735:G:A, l:55052744:G:A, l:55052746:G:A, l:55052758:C:T, l:55052771:C:T, l:55052779:G:A, l:55056028:C:A, l:55056068:G:T, l:55056085:A:G, l:55056087:C:A, l:55056091:G:A, l:55056148:C:T, l:55056149:G:A, l:55056168:C:G, l:55056185:C:T, l:55057340:G:A, l:55057343:G:A, l:55057368:C:T, l:55057392:C:A, l:55057401:GC:G, l:55057403:C:T, l:55057404:G:A, l:55057433:G:C, l:55057439:A:T, l:55057454:G:A, l:55057470:T:C, l:55057475:TCA:T, l:55057512:C:G, l:55058066:C:T, l:55058110:T:G, l:55058127:C:G, l:55058150:A:G, l:55058189:C:T, l:55058191:C:T, l:55058538:C:G, l:55058543:C:G, l:55058549:C:T, l:55058570:C:T, l:55058587:G:C, l:55058590:G:C, l:55058627:C:T, l:55058630:C:T, l:55058631:G:A, l:55058638:G:C, l:55058639:C:T, l:55059492:G:T, l:55059510:C:T, l:55059537:G:A, l:55059538:G:A, l:55059603:C:T, l:55059649:G:T, l:55059660:A:G, l:55061485:G:A, l:55061498:A:G, l:55061501:C:T, l:55061558:T:G, l:55063384:G:A, l:55063450:G:A, l:55063459:A:G, l:55063474:A:G, l:55063480:C:T, l:55063542:C:A, l:55063543:C:T, l:55039845:C:A, l:55039902:T:TG, l:55039903:C:CT, l:55039910:C:G, l:55039925:G:GCGCA, l:55039926:C:G, l:55039940:G:T, l:55039950:A:G, l:55039959:T:A, l:55039979:G:A, l:55039980:AG:A, l:55039989:GC:G, l:55040034:G:A, l:55043846:C:T, l:55043847:C:T, l:55043849:T:TG, l:55043870:G:T, 1:55043901:0:6, l:55043906:T:G, l:55043912:C:T, l:55043915:A:C, l:55043921:C:T, l:55043924:C:T, l:55043925:G:A, l:55043925:G:T, l:55043933:G:A, l:55043945:C:T, l:55043946:G:A, l:55043949:G:A, l:55043951:G:A, l:55043970:T:C, l:55043976:T:C, l:55043987:C:T, l:55044012:T:A, l:55044013:G:A, l:55044020:G:A, l:55046521:A:C, l:55046527:T:C, l:55046535:C:T, l:55046549:C:G, l:55046552:C:G, l:55046570:CTT:C, l:55046587:C:T, l:55046594:C:A, l:55046602:G:A, l:55046610:C:T, l:55046622:C:T, l:55046640:C:T, l:55046643:C:T, l:55052283:G:T, l:55052284:G:A, l:55052310:G:C, l:55052318:C:CAT, l:55052325:A:G, l:55052335:G:A, l:55052358:G:A, l:55052370:G:A, l:55052382:G:A, l:55052391:G:A, l:55052397:C:T, l:55052412:G:T, l:55052648:A:C, l:55052648:A:G, l:55052650:G:A, l:55052651:CCAGCAAGT:C, l:55052689:G:A, l:55052698:G:A, 1:55052701:0:1, l:55052702:G:A, l:55052713:G:A, l:55052716:G:A, l:55052717:C:T, l:55052718:CA:C, l:55052734:C:T, l:55052735:G:A, l:55052739:C:A, l:55052746:G:A, l:55052746:GT:G, l:55052749:C:T, l:55052752:A:T, l:55052764:A:T, l:55052771:C:T, l:55052779:G:A, l:55052783:C:A, l:55056028:C:A, l:55056040:C:A, l:55056041:T:G, l:55056056:C:T, l:55056085:A:G, l:55056096:C:A, l:55056100:C:T, l:55056107:C:A, l:55056115:G:T, l:55056133:G:C, l:55056139:G:A, l:55056158:C:T, l:55056170:C:A, l:55057361:G:A, l:55057365:A:G, 1 :55057403 :C:T, l:55057404:G:A, l:55057415:C:T, l:55057433:G:C, 1:55057433 :G:T, l:55057454:G:A, l:55057467:G:A, l:55057468:C:A, l:55057478:C:T, l:55057482:G:A, l:55057484:G:A, l:55057503:C:T, l:55057505:C:A, l:55057514:G:A, l:55058066:C:T, l:55058102:T:C, l:55058106:C:A, l:55058125:A:G, l:55058128:A:C, l:55058149:G:A, l:55058153:A:G, l:55058155:C:T, l:55058165:C:A, l:55058206:G:A, l:55058515:C:G, l:55058522:G:A, l:55058528:T:C, l:55058534:C:G, l:55058538:C:T, l:55058541:G:A, l:55058543:C:G, l:55058549:C:T, l:55058550:G:A, l:55058558:A:G, l:55058567:G:A, l:55058570:C:T, l:55058585:G:A, l:55058589:A:G, l:55058619:G:C, l:55058620:T:A, l:55058627:C:T, l:55058628:G:A, l:55058628:G:T, l:55058630:C:T, l:55058631:G:A, l:55058636:G:A, l:55058639:C:T, l:55058640:G:C, l:55059492:G:T, l:55059493:G:A, l:55059510:C:T, l:55059522:G:A, l:55059540:G:A, l:55059546:G:A, l:55059549:A:T, l:55059564:C:G, l:55059583:G:T, l:55059627:C:T, l:55059661:C:T, l:55061378:G:A, l:55061383:T:G, l:55061437:C:T, l:55061474:C:A, l:55061485:G:A, l:55061548:C:T, l:55061557:G:A, l:55063375:G:A, l:55063384:G:A, l:55063411:A:C, l:55063414:GC:G, l:55063417:C:T, l:55063420:C:G, l:55063421:C:T, l:55063459:A:G, 1:55063463 :C:T, l:55063465:T:C, l:55063474:A:G, l:55063480:C:T, l:55063483:G:A, l:55063486:G:A, l:55063519:G:A, l:55063527:CG:C, l:55063535:T:C, l:55063542:C:A, l:55063543:C:T, l:55063544:G:A, l:55063570:C:T, l:55063574:A:C, l:55063574:A:T, l:55039890:T:G, l:55039902:T:TGC, l:55039910:C:G, l:55039917:G:A, l:55039923:G:C, l:55039925:G:GCGCA, l:55039937:G:A, l:55039940:G:T, l:55039943:G:C, l:55039979:G:A, l:55040006:G:T, l:55040024:AC:A, l:55040038:CG:C, l:55040046:T:C, l:55043854:G:T, l:55043857:G:T, l:55043865:C:T, l:55043870:G:A, l:55043876:GT:G, l:55043901:C:G, l:55043909:G:C, l:55043912:C:T, l:55043915:A:C, 1:55043921:C:T, l:55043922:G:A, l:55043924:C:T, l:55043925:G:A, l:55043925:G:T, l:55043933:G:A, l:55043945:C:T, l:55043946:G:A, l:55043948:C:T, l:55043949:G:A, l:55043949:G:T, l:55043952:G:T, l:55043976:T:C, l:55044006:T:A, l:55044013:G:A, l:55044016:T:G, l:55044020:G:A, l:55044026:C:G, l:55044035:G:T, l:55044036:T:C, l:55046521:A:C, l:55046524:C:A, l:55046527:T:C, l:55046531:GT:G, l:55046535:C:T, l:55046547:T:C, l:55046549:C:G, l:55046572:T:C, l:55046577:C:A, l:55046578:A:G, l:55046579:G:C, l:55046587:C:T, l:55046590:G:A, l:55046591:G:A, l:55046594:C:A, l:55046599:A:G, l:55046600:G:T, l:55046601:C:T, l:55046602:G:A, l:55046605:T:C, l:55046608:C:A, l:55046610:C:A, l:55046622:C:T, l:55046639:G:T, l:55046640:C:T, l:55046643:C:T, l:55046646:G:A, l:55046647:G:A, l:55052284:G:A, l:55052300:G:GT, l:55052311:A:G, l:55052317:G:C, l:55052318:C:CAT, l:55052333:C:A, l:55052334:C:T, l:55052335:G:A, l:55052346:G:A, l:55052353:T:C, l:55052356:T:C, l:55052364:G:A, l:55052370:G:A, l:55052380:C:A, l:55052382:G:A, l:55052390:C:G, l:55052391:G:A, l:55052395:C:A, l:55052395:C:T, l:55052397:C:A, l:55052397:C:T, l:55052398:G:A, l:55052409:C:G, l:55052412:G:T, l:55052648:A:C, l:55052654:G:T, l:55052662:G:C, l:55052666:G:A, l:55052672:G:A, l:55052685:AG:A, l:55052689:G:A, l:55052689:G:T, l:55052698:G:A, l:55052701:C:T, l:55052702:G:A, l:55052704:G:GA, l:55052710:G:A, l:55052713:G:A, l:55052732:T:C, l:55052734:C:T, 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[0065] 1:55052284:6:0, l:55052301:T:C, l:55052306:CCTAGA:C, l:55052318:C:CAT, l:55052326:G:A, l:55052333:C:A, l:55052335:G:A, l:55052346:G:T, l:55052359:T:C, l:55052370:G:A, l:55052382:G:A, l:55052385:G:T, l:55052397:C:T, l:55052398:G:A, l:55052409:C:G, l:55052412:G:T, l:55052648:A:C, l:55052649:GGCCA:G, l:55052650:G:A, l:55052651:CCAGCAAGT:C, l:55052675:C:G, l:55052689:G:T, l:55052698:G:A, l:55052699:G:A, l:55052701:C:T, l:55052716:G:A, l:55052734:C:T, l:55052735:G:A, l:55052739:C:A, l:55052743:C:T, l:55052744:G:A, l:55052746:G:A, l:55052746:GT:G, l:55052749:C:T, l:55052764:A:G, l:55052771:C:T, l:55052774:T:C, l:55052779:G:A, l:55055993:G:T, l:55055996:T:G, l:55056028:C:A, l:55056029:C:T, l:55056040:C:A, l:55056070:T:G, l:55056076:C:T, l:55056077:G:A, l:55056077:G:C, l:55056085:A:G, l:55056091:G:A, l:55056092:C:T, l:55056139:G:T, l:55056148:C:T, l:55056170:C:A, l:55057386:T:C, l:55057403:C:T, l:55057404:G:A, l:55057415:C:T, l:55057433:G:C, l:55057433:G:T, l:55057452:G:A, l:55057454:G:A, l:55057464:C:A, l:55057475:TCA:T, l:55057481:A:C, l:55057505:C:A, l:55057514:G:A, l:55058036:G:T, l:55058066:C:T, l:55058083:G:A, 1:55058102:7:0, l:55058105:A:G, l:55058106:C:A, l:55058109:C:G, l:55058125:A:G, l:55058149:G:A, 1:55058155:0:7, l:55058189:C:G, l:55058497:A:C, l:55058503:G:A, l:55058515:C:G, 1:55058528:7:0, l:55058536:C:G, l:55058538:C:G,

[0066] 1:55058538:0:7, l:55058543:C:G, 1:55058549:0:7, l:55058554:G:A, l:55058567:G:A,

[0067] 1:55058570:0:7, l:55058589:A:G, l:55058591:C:G, l:55058625:A:G, l:55058628:G:A,

[0068] 1:55058630:0:7, l:55058631:G:A, l:55058636:G:A, 1:55058639:0:7, l:55058640:G:C, l:55058640:G:7, l:55059511:G:A, l:55059522:G:A, 1:55059523:0:07, l:55059529:G:7, l:55059547:C:G, 1:55059568:7:0, 1:55061383:7:0, l:55061426:7:A, 1:55061437:0:7, l:55061485:G:A, l:55061500:G:A, 1:55061548:0:7, l:55061552:A:G, l:55061557:G:A, l:55063375:G:A, l:55063384:G:A, l:55063391:G:A, l:55063459:A:G, 1:55063463:0:7,

[0069] 1:55063465:7:0, 1:55063480:0:7, l:55063486:G:A, 1:55063493:0:7, l:55063519:G:A, l:55063527:CG:C, l:55063542:C:A, 1:55063543:0:7, 1:55063570:0:7, l:55039838:A:G, l:55039838:A:T, l:55039839:T:G, l:55039840:G:T, l:55039842:G:T, l:55039860:G:T, l:55039866:G:C, l:55039870:G:A, l:55039902:T:TGC, l:55039902:T:C, l:55039905:T:C, l:55039910:C:G, l:55039910:C:T, l:55039917:G:A, l:55039923:G:A, l:55039925:G:T, l:55039925:G:GCGCA, l:55039926:C:T, l:55039937:G:A, l:55039940:G:C, l:55039940:G:T, l:55039947:A:G, l:55039950:A:G, l:55039951:C:A, l:55039953:A:T, l:55039959:T:A, l:55039967:G:A, l:55039968:C:T, l:55039973:C:T, l:55039979:G:A, l:55039985:G:A, l:55039989:G:A, l:55039995:C:A, l:55040006:G:T, l:55040021:G:A, l:55040021:G:C, l:55040024:AC:A, l:55040034:G:A, l:55040036:T:C, l:55040036:T:G, l:55040038:C:G, l:55040045:G:A, l:55043841:A:G, l:55043847:C:T, l:55043851:G:A, l:55043854:G:T, l:55043864:A:G, l:55043868:A:G, l:55043870:G:A, l:55043870:G:GT, l:55043874:T:C, l:55043877:T:A, l:55043901:C:G, 1:55043903 :C:T, l:55043904:A:G, l:55043912:C:A, l:55043912:C:T, l:55043913:G:T, l:55043915:A:C, l:55043915:A:G, l:55043918:G:A, l:55043921:C:T, l:55043922:G:A, l:55043924:C:T, l:55043925:G:A, l:55043925:G:T, l:55043930:C:T, l:55043933:G:A, l:55043934:C:G, l:55043940:C:T, l:55043942:GC:G, l:55043942:G:A, l:55043945:C:T, l:55043946:G:A, l:55043948:C:T, l:55043949:G:A, l:55043951:G:A, l:55043952:G:A, l:55043952:G:T, 1:55043954:7:0, l:55043964:A:7,

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[0071] 1:55058111:0:1, l:55058113:GC:G, l:55058119:G:C, l:55058120:A:G, l:55058120:A:T, l:55058125:A:C, l:55058125:A:G, l:55058139:G:A, l:55058144:C:T, l:55058148:G:C, l:55058149:G:A, l:55058153:A:G, l:55058155:C:T, l:55058156:G:A, l:55058158:G:A, l:55058158:G:T, l:55058165:C:A, l:55058165:C:T, l:55058168:C:T, l:55058176:G:A, l:55058176:G:T, l:55058180:C:A, l:55058188:C:T, l:55058189:C:G, l:55058189:C:T,

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l:55057364:C:A, l:55057364:C:T, l:55057365:A:G, l:55057374:C:T, l:55057388:G:A, l:55057389:G:A, l:55057403:C:T, l:55057404:G:A, l:55057433:G:C, l:55057433:G:T, l:55057464:C:G, l:55057478:C:T, l:55057499:G:C, l:55057505:C:A, l:55057511:G:A, l:55057514:G:A, l:55057515:G:T, l:55058036:G:T, l:55058066:C:T, l:55058083:G:A, l:55058102:T:C, l:55058106:C:A, l:55058113:GC:G, l:55058125:A:G, l:55058139:G:A, l:55058149:G:A, 1:55058155:0:1, l:55058165:C:A, l:55058189:C:G, l:55058209:G:A, l:55058499:G:A, l:55058515:C:G, l:55058522:G:A, l:55058526:G:C, l:55058528:T:C, l:55058534:C:T, l:55058536:C:G, l:55058538:C:T, l:55058541:G:A, l:55058543:C:G, l:55058549:C:T, l:55058570:C:T, l:55058589:A:G, l:55058591:C:G, l:55058620:TG:T, l:55058627:C:T, l:55058628:G:A, l:55058630:C:T, l:55058631:G:A, l:55058636:G:A, l:55058639:C:T, l:55058640:G:C, l:55058640:G:T, l:55058645:G:A, l:55059484:A:C, l:55059492:G:T, l:55059496:G:A, l:55059504:G:T, l:55059531:G:A, l:55059550:T:C, l:55059598:C:T, l:55059603:C:T, l:55059627:C:T, l:55061388:C:G, l:55061426:T:A, l:55061474:C:A, l:55061485:G:A, l:55061492:G:A, l:55061500:G:A, l:55061501:C:T, l:55061548:C:T, l:55061555:A:C, l:55061557:G:A, l:55063375:G:A, l:55063382:G:C, l:55063391:G:A, l:55063417:C:T, l:55063420:C:G, l:55063457:A:G, l:55063459:A:G, l:55063463:C:T, l:55063465:T:C, l:55063474:A:G, l:55063480:C:T, l:55063486:G:A, l:55063519:G:A, l:55063542:C:A, 1 :55063543 :C:T, l:55063544:G:A, l:55063570:C:T, l:55063574:A:C, l:55039841:G:A, l:55039923:G:C, l:55039926:C:G, l:55039940:G:T, l:55040021:G:C, l:55043906:T:G, l:55043912:C:T, l:55043922:G:A, l:55043925:G:A, l:55043945:C:T, l:55043946:G:A, l:55043952:G:T, l:55043991:T:C, l:55044020:G:A, l:55046548:A:G, l:55046549:C:G, l:55046552:C:G, l:55046594:C:A, l:55046601:C:T, l:55046602:G:A, l:55046622:C:T, l:55046643:C:T, l:55046647:G:GT, l:55052283:G:T, l:55052318:C:CAT, l:55052335:G:A, l:55052364:G:A, l:55052370:G:A, l:55052408:A:T, l:55052660:G:T, l:55052689:G:A, l:55052689:G:T, l:55052698:G:A, l:55052701:C:T, l:55052706:T:G, l:55052713:G:A, l:55052732:T:C, l:55052734:C:T, l:55052744:G:A, l:55052746:G:A, l:55052746:G:C, l:55052749:C:T, l:55052764:A:T, l:55052767:G:A, l:55052771:C:T, l:55055991:A:G, l:55056028:C:A, l:55056029:C:T, l:55056037:C:A, l:55056037:C:T, l:55056040:C:A, l:55056043:G:A, l:55056056:C:T, l:55056074:G:A, l:55056134:C:T, l:55056139:G:A, l:55056146:T:A, l:55056154:G:A, l:55056170:C:A, l:55056175:G:T, l:55056187:G:A, l:55057329:A:T, l:55057351:C:CAATG, l:55057368:C:T, l:55057386:T:C, l:55057403:C:T, 1:55057452 :G:T, l:55057499:G:C, l:55057505:C:A, l:55057507:C:G, l:55058083:G:A, l:55058106:C:A, 1:55058113:60:6, l:55058120:A:T, l:55058139:G:A, l:55058149:G:A, l:55058165:C:A, l:55058193:CAG:C, l:55058499:G:A, l:55058522:G:A, l:55058549:C:T, l:55058567:G:A, l:55058589:A:G, l:55058619:G:C, l:55058620:TG:T, l:55058628:G:T, l:55058639:C:T, l:55058640:G:C, l:55058640:G:T, l:55059522:G:A, l:55059523:C:CT, l:55059529:G:T, l:55059531:G:A, l:55059625:C:A, l:55059627:C:T, l:55059661:C:T, l:55061474:C:A, l:55061509:C:G, l:55061548:C:T, l:55061557:G:A, l:55063375:G:A, l:55063384:G:A, l:55063456:G:T, l:55063480:C:T, l:55063528:G:T, and l:55063542:C:A, or an mRNA molecule produced therefrom, or a cDNA molecule produced from the mRNA molecule. In some embodiments, the PCSK9 variant nucleic acid molecule comprises the genetic variation rsll591147 (Arg46Leu). In some embodiments, the subject being treated is heterozygous for the PCSK9 variant nucleic acid molecule. In some embodiments, the subject being treated is PCSK9 reference.

[0073] For subjects that are genotyped or determined to be PCSK9 reference or only heterozygous for a PCSK9 variant nucleic acid molecule, such subjects have an increased risk of developing aneurysms and are candidates for gene editing in which the one or two copies of the PCSK9 reference gene are replaced with a copy of a PCSK9 variant nucleic acid molecule.

[0074] In any of the embodiments described herein, the LPA variant nucleic acid molecule can be any nucleic acid molecule (such as, a genomic nucleic acid molecule, an mRNA molecule, or a cDNA molecule produced from an mRNA molecule) that results in increased Lp(a) expression or level. In some embodiments, the LPA variant nucleic acid molecule results in increased or aberrant expression or activity of LPA mRNA or polypeptide. In some embodiments, the LPA variant nucleic acid molecule is associated with an increased in vitro response to LPA ligands compared with reference LPA. In some embodiments, the LPA variant nucleic acid molecule is a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, an in-frame indel variant, or a variant that encodes a truncated Lp(a). In some embodiments, the LPA variant nucleic acid molecule is a missense variant nucleic acid molecule. In some embodiments, the LPA variant nucleic acid molecule comprises a single nucleotide polymorphism (SNP). In some embodiments, the LPA variant nucleic acid molecule comprises a variation in a coding region. In some embodiments, the LPA variant nucleic acid molecule does not comprise a variation in a non-coding region, except for a splice acceptor region (two bases before the start of any exon except the first). In some embodiments, the LPA variant nucleic acid molecule results or is predicted to result in a premature truncation of an Lp(a) compared to the reference LPA. In some embodiments, the LPA variant nucleic acid molecule is a variant that is predicted to increase Lp(a) protein function or expression (and hence, in this case, detrimental to the human) by in vitro prediction algorithms such as Polyphen, SIFT, or similar algorithms. In some embodiments, the LPA variant nucleic acid molecule is a variant that causes or is predicted to cause a nonsynonymous amino acid substitution in an LPA nucleic acid molecule and whose allele frequency is less than 1 / 100 alleles in the population from which the subject is selected. In some embodiments, the LPA variant nucleic acid molecule is any rare missense variant (allele frequency < 0.1%; or 1 in 1,000 alleles), or any splice-site, stop-gain, start-loss, stop-loss, frameshift, or in-frame indel, or other frameshift LPA variant.

[0075] In any of the embodiments described herein, the LPA variant genomic nucleic acid molecule may include one or more variations at any of the positions of chromosome 6 (i.e., positions 160,531,482 to 160,664,275) using the nucleotide sequence of the LPA reference genomic nucleic acid molecule in the GRCh38 / hg38 human genome assembly (see, EN5G00000198670.13, ENST00000316300.10 annotated in the in the Ensembl database (URL: world wide web at "https: / / useast.ensembl.org / Homo_sapiens / Gene / Summary? g=ENSG00000198670;r=6:160531482-160664275;t=ENST00000316300")) as a reference sequence. The sequences provided in these transcripts for the LPA genomic nucleic acid molecule are only exemplary sequences. Other sequences for the LPA genomic nucleic acid molecule are also possible.

[0076] In any of the embodiments described herein, the LPA variant nucleic acid molecule may comprise any one or more of the following genetic variations in the genomic nucleic acid molecule (referring to the chromosome:positions set forth in the GRCh38 / hg38 human genome assembly): 6:160426539:G:A, 6:160756411:C:T, 6:160768039:G:A, 6:160830908:A:G, 6:160545527:G:A, 6:160714714:T:G, 6:160478017:C:CA, 6:160591981:T:C, 6:160829269:A:G, 6:160488635:T:A, 6:160521894:G:A, 6:160404898:A:T, 6:160533768:C:T, 6:160871806:A:C, 6:160410764:G:A, 6:160834636:A:G, 6:160470865:C:A, 6:160741258:A:G, 6:160299772:G:C, 6:160793494:G:A, 6:160610100:G:A, 6:160590967:G:C, 6:160122285:C:T, 6:160836921:C:T, 6:160532105:T:A, 6:160532105:T:C, 6:160532610:A:G, 6:160577167:G:A, 6:160649621:C:A, 6:160738334:T:G, 6:160741374:T:C, 6:160864728:A:G, 6:160668275:C:T, 6:160469318:A:T, 6:160596331:G:A, 6:160576086:A:T, 6:160667924:G:A, 6:160666620:T:G, 6:160716958:G:A, 6:160657862:T:C, 6:160591773:T:C, and 6:160426539:G:A, or an mRNA molecule produced therefrom, or a cDNA molecule produced from the mRNA molecule. Such genetic variants are within the LPA gene or a gene closely linked to affecting Lp(a) protein expression level. In some embodiments, the LPA variant nucleic acid molecule may comprise rsl0455872 and / or rs3798220, or an mRNA molecule produced therefrom, or a cDNA molecule produced from the mRNA molecule. In some embodiments, the subject being treated is heterozygous for the LPA variant nucleic acid molecule. In some embodiments, the subject being treated is homozygous for the LPA variant nucleic acid molecule.

[0077] For subjects that are genotyped or determined to be heterozygous or homozygous for an LPA variant nucleic acid molecule, such subjects have an increased risk of developing aneurysms and are candidates for gene editing in which the one or two copies of the LPA reference gene are disrupted (i.e., disrupted to the point that LPA expression is reduced to an acceptable level or eliminated altogether).

[0078] In any of the embodiments described herein, the subject in whom an aneurysm is prevented, the progression of an aneurysm is prevented, or a complication of an aneurysm is prevented may be anyone at risk for developing aneurysms including, but not limited to, subjects with a genetic predisposition for developing aneurysms. Additional risk factors for aneurysms include, but are not limited to, age, gender, high blood pressure or hypertension, genetics or predisposition, smoking, atherosclerosis, hyperlipidemia, coronary artery disease, stroke, illicit drug use or drug abuse, trauma, head trauma, pregnancy, bacterial infections including endocarditis, vasculitis, and untreated syphilis, bicuspid aortic valve, diabetes, poor diet, obesity, a history of aneurysms, risk of rupturing, including dissection, size, shape, and pattern of the aneurysm, location of the aneurysm. In some embodiments, administering an APOC3 inhibitor to a subject having an aneurysm may be carried out to prevent development of another occurrence of an aneurysm in a subject who has already had an aneurysm. In any of the embodiments described herein, the methods can be used to improve aneurysms.

[0079] In any of the embodiments described herein, the APOC3 predicted loss-of-function polypeptide can be any APOC3 polypeptide having a partial loss-of-function, a complete loss-of- function, a predicted partial loss-of-function, or a predicted complete loss-of-function.

[0080] Any one or more (i.e., any combination) of the APOC3 variant nucleic acid molecules described herein can be used within any of the methods described herein to determine whether a subject has an increased or decreased risk of developing aneurysms. The combinations of particular variants can form a mask used for statistical analysis of the particular correlation of APOC3 and an increased or decreased risk of developing an aneurysm. In some embodiments, the mask used for statistical analysis of the particular correlation of APOC3 and an increased or decreased risk of developing an aneurysm can exclude any one or more of these APOC3 variant nucleic acid molecules described herein.

[0081] In any of the embodiments described herein, the subject can have an aneurysm. In any of the embodiments described herein, the subject can be at risk of developing an aneurysm. In any of the embodiments described herein, the subject can be at risk of progression of an aneurysm. In any of the embodiments described herein, the aneurysm may be an abdominal aortic aneurysm, a thoracic aortic aneurysm, a cerebral aneurysm, a carotid aneurysm, a popliteal aneurysm, a mesenteric aneurysm, or a splenic aneurysm. In some embodiments, the aneurysm is an abdominal aortic aneurysm. In some embodiments, the aneurysm is a thoracic aortic aneurysm. In some embodiments, the aneurysm is a cerebral aneurysm. In some embodiments, the aneurysm is a carotid aneurysm. In some embodiments, the aneurysm is a popliteal aneurysm. In some embodiments, the aneurysm is a mesenteric aneurysm. In some embodiments, the aneurysm is a splenic aneurysm.

[0082] In any of the embodiments described herein, the methods can be used to treat a complication or co-morbidity of aneurysms, or reduce the risk of developing the same. Complications and co-morbidities of aneurysms include, but are not limited to, cholecystolithiasis, chronic obstructive pulmonary disease, hernias, vasospasm, smoking, hypertension, alcohol abuse, gender, ethnical aspects, time between aneurysm rupture and treatment, neurological injury, peripheral artery disease, atherosclerosis, inflammatory arterial disorders, noninflammatory arteriopathies, polycystic kidney disease, coarctation of the aorta, and Ehlers-Danlos syndrome.

[0083] The methods described herein may also be used to treat or prevent acquired aortic valve stenosis (AoS).

[0084] The present disclosure provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, the methods comprising administering an APOC3 inhibitor to the subject. The APOC3 inhibitor can be an inhibitory nucleic acid molecule (e.g., antisense, siRNA, shRNA), a small molecule, an antibody, or compound(s) for gene editing.

[0085] In some embodiments, the APOC3 inhibitor comprises an inhibitory nucleic acid molecule. Examples of inhibitory nucleic acid molecules include, but are not limited to, antisense nucleic acid molecules, small interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs). Such inhibitory nucleic acid molecules can be designed to target any region of an APOC3 nucleic acid molecule. In some embodiments, the antisense RNA, siRNA, or shRNA hybridizes to a sequence within an APOC3 genomic nucleic acid molecule or mRNA molecule and decreases expression of the APOC3 polypeptide in a cell in the subject. In some embodiments, the APOC3 inhibitor comprises an antisense molecule that hybridizes to an APOC3 genomic nucleic acid molecule or mRNA molecule and decreases expression of the APOC3 polypeptide in a cell in the subject. In some embodiments, the APOC3 inhibitor comprises an siRNA that hybridizes to an APOC3 genomic nucleic acid molecule or mRNA molecule and decreases expression of the APOC3 polypeptide in a cell in the subject. In some embodiments, the APOC3 inhibitor comprises an shRNA that hybridizes to an APOC3 genomic nucleic acid molecule or mRNA molecule and decreases expression of the APOC3 polypeptide in a cell in the subject.

[0086] The inhibitory nucleic acid molecules can comprise RNA, DNA, or both RNA and DNA. The inhibitory nucleic acid molecules can also be linked or fused to a heterologous nucleic acid sequence, such as in a vector, or a heterologous label. For example, the inhibitory nucleic acid molecules can be within a vector or as an exogenous donor sequence comprising the inhibitory nucleic acid molecule and a heterologous nucleic acid sequence. The inhibitory nucleic acid molecules can also be linked or fused to a heterologous label. The label can be directly detectable (such as, for example, fluorophore) or indirectly detectable (such as, for example, hapten, enzyme, or fluorophore quencher). Such labels can be detectable by spectroscopic, photochemical, biochemical, immunochemical, or chemical means. Such labels include, for example, radiolabels, pigments, dyes, chromogens, spin labels, and fluorescent labels. The label can also be, for example, a chemiluminescent substance; a metal-containing substance; or an enzyme, where there occurs an enzyme-dependent secondary generation of signal. The term "label" can also refer to a "tag" or hapten that can bind selectively to a conjugated molecule such that the conjugated molecule, when added subsequently along with a substrate, is used to generate a detectable signal. For example, biotin can be used as a tag along with an avidin or streptavidin conjugate of horseradish peroxidate (HRP) to bind to the tag, and examined using a calorimetric substrate (such as, for example, tetramethylbenzidine (TMB)) or a fluorogenic substrate to detect the presence of HRP. Exemplary labels that can be used as tags to facilitate purification include, but are not limited to, myc, HA, FLAG or 3XFLAG, 6XHis or polyhistidine, glutathione-S-transferase (GST), maltose binding protein, an epitope tag, or the Fc portion of immunoglobulin. Numerous labels include, for example, particles, fluorophores, haptens, enzymes and their calorimetric, fluorogenic and chemiluminescent substrates and other labels.

[0087] The inhibitory nucleic acid molecules can comprise, for example, nucleotides or nonnatural or modified nucleotides, such as nucleotide analogs or nucleotide substitutes. Such nucleotides include a nucleotide that contains a modified base, sugar, or phosphate group, or that incorporates a non-natural moiety in its structure. Examples of non-natural nucleotides include, but are not limited to, dideoxynucleotides, biotinylated, aminated, deaminated, alkylated, benzylated, and fluorophor-labeled nucleotides.

[0088] The inhibitory nucleic acid molecules can also comprise one or more nucleotide analogs or substitutions. A nucleotide analog is a nucleotide which contains a modification to either the base, sugar, or phosphate moieties. Modifications to the base moiety include, but are not limited to, natural and synthetic modifications of A, C, G, and T / U, as well as different purine or pyrimidine bases such as, for example, pseudouridine, uracil-5-yl, hypoxanthin-9-yl (I), and 2-aminoadenin-9-yl. Modified bases include, but are not limited to, 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo (such as, for example, 5-bromo), 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine, 7-methyladenine, 8-azaguanine, 8-azaadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, and 3-deazaadenine.

[0089] Nucleotide analogs can also include modifications of the sugar moiety. Modifications to the sugar moiety include, but are not limited to, natural modifications of the ribose and deoxy ribose as well as synthetic modifications. Sugar modifications include, but are not limited to, the following modifications at the 2' position: OH; F; O-, S-, or N-alkyl; O-, S-, or N-alkenyl; O-, S- or N-alkynyl; or O-a I ky l-O-al kyl, wherein the alkyl, alkenyl, and alkynyl may be substituted or unsubstituted Ci-ioal ky I or Cz-ioalkenyl, and Cz-ioalkynyl. Exemplary 2' sugar modifications also include, but are not limited to, -O[(CH2)nO]mCH3, -O(CH2)nOCH3, -O(CH2)nNH2, -O(CH2)nCH3, -O(CH2)n-ONH2, and -O(CH2)nON[(CH2)nCH3)]2, where n and m, independently, are from 1 to about 10. Other modifications at the 2' position include, but are not limited to, Ci-ioa I kyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH3, OCN, Cl, Br, CN, CF3, OCF3, SOCH3, SO2CH3, ONO2, NO2, N3, NH2, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties of an oligonucleotide, or a group for improving the pharmacodynamic properties of an oligonucleotide, and other substituents having similar properties. Similar modifications may also be made at other positions on the sugar, particularly the 3' position of the sugar on the 3' terminal nucleotide or in 2'-5' linked oligonucleotides and the 5' position of 5' terminal nucleotide. Modified sugars can also include those that contain modifications at the bridging ring oxygen, such as CH2 and S. Nucleotide sugar analogs can also have sugar mimetics, such as cyclobutyl moieties in place of the pentofu ranosyl sugar.

[0090] Nucleotide analogs can also be modified at the phosphate moiety. Modified phosphate moieties include, but are not limited to, those that can be modified so that the linkage between two nucleotides contains a phosphorothioate, chiral phosphorothioate, phosphorodithioate, phosphotriester, aminoalkylphosphotriester, methyl and other alkyl phosphonates including 3'- alkylene phosphonate and chiral phosphonates, phosphinates, phosphoramidates including 3'- amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates. These phosphate or modified phosphate linkage between two nucleotides can be through a 3'-5' linkage or a 2'-5' linkage, and the linkage can contain inverted polarity such as 3'-5' to 5'-3' or 2'-5' to 5'-2'. Various salts, mixed salts, and free acid forms are also included. Nucleotide substitutes also include peptide nucleic acids (PNAs).

[0091] In some embodiments, the antisense nucleic acid molecules are gapmers, whereby the first one to seven nucleotides at the 5' and 3' ends each have 2'-methoxyethyl (2'-MOE) modifications. In some embodiments, the first five nucleotides at the 5' and 3' ends each have 2'-MOE modifications. In some embodiments, the first one to seven nucleotides at the 5' and 3' ends are RNA nucleotides. In some embodiments, the first five nucleotides at the 5' and 3' ends are RNA nucleotides. In some embodiments, each of the backbone linkages between the nucleotides is a phosphorothioate linkage.

[0092] In some embodiments, the siRNA molecules have termini modifications. In some embodiments, the 5' end of the antisense strand is phosphorylated. In some embodiments, 5'- phosphate analogs that cannot be hydrolyzed, such as 5'-(E)-vinyl-phosphonate are used.

[0093] In some embodiments, the siRNA molecules have backbone modifications. In some embodiments, the modified phosphodiester groups that link consecutive ribose nucleosides have been shown to enhance the stability and in vivo bioavailability of siRNAs The non-ester groups (-OH, =0) of the phosphodiester linkage can be replaced with sulfur, boron, or acetate to give phosphorothioate, boranophosphate, and phosphonoacetate linkages. In addition, substituting the phosphodiester group with a phosphotriester can facilitate cellular uptake of siRNAs and retention on serum components by eliminating their negative charge. In some embodiments, the siRNA molecules have sugar modifications. In some embodiments, the sugars are deprotonated (reaction catalyzed by exo- and endonucleases) whereby the 2'- hydroxyl can act as a nucleophile and attack the adjacent phosphorous in the phosphodiester bond. Such alternatives include 2'-O-methyl, 2'-O-methoxyethyl, and 2'-fluoro modifications.

[0094] In some embodiments, the siRNA molecules have base modifications. In some embodiments, the bases can be substituted with modified bases such as pseudouridine, 5'-methylcytidine, N6-methyladenosine, inosine, and N7-methylguanosine.

[0095] In some embodiments, the siRNA molecules are conjugated to lipids. Lipids can be conjugated to the 5' or 3' termini of siRNA to improve their in vivo bioavailability by allowing them to associate with serum lipoproteins. Representative lipids include, but are not limited to, cholesterol and vitamin E, and fatty acids, such as palmitate and tocopherol.

[0096] In some embodiments, a representative siRNA has the following formula:

[0097] Sense: mN*mN* / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / *mN* / 32FN /

[0098] Antisense: / 52FN / * / i2FN / *mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN*N*N wherein: "N" is the base; "2F" is a 2'-F modification; "m" is a 2'-O-methyl modification, "I" is an internal base; and is a phosphorothioate backbone linkage.

[0099] In some embodiments, the APOC3 inhibitor comprises ARO-APOC3 (Arrowhead Pharmaceuticals), olezarsen (lonis Pharmaceuticals), or WAYLIVRA® (volanesorsen) (lonis Pharmaceuticals). In some embodiments, the APOC3 inhibitor comprises ARO-APOC3. In some embodiments, the APOC3 inhibitor comprises olezarsen. In some embodiments, the APOC3 inhibitor comprises volanesorsen.

[0100] In any of the embodiments described herein, the inhibitory nucleic acid molecules may be administered, for example, as one to two hour i.v. infusions or s.c. injections. In any of the embodiments described herein, the inhibitory nucleic acid molecules may be administered at dose levels that range from about 50 mg to about 900 mg, from about 100 mg to about 800 mg, from about 150 mg to about 700 mg, or from about 175 to about 640 mg (2.5 to 9.14 mg / kg; 92.5 to 338 mg / m2- based on an assumption of a body weight of 70 kg and a conversion of mg / kg to mg / m2dose levels based on a mg / kg dose multiplier value of 37 for humans).

[0101] The present disclosure also provides vectors comprising any one or more of the inhibitory nucleic acid molecules. In some embodiments, the vectors comprise any one or more of the inhibitory nucleic acid molecules and a heterologous nucleic acid. The vectors can be viral or nonviral vectors capable of transporting a nucleic acid molecule. In some embodiments, the vector is a plasmid or cosmid (such as, for example, a circular double-stranded DNA into which additional DNA segments can be ligated). In some embodiments, the vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Expression vectors include, but are not limited to, plasmids, cosmids, retroviruses, adenoviruses, adeno- associated viruses (AAV), plant viruses such as cauliflower mosaic virus and tobacco mosaic virus, yeast artificial chromosomes (YACs), Epstein-Barr (EBV)-derived episomes, and other expression vectors known in the art.

[0102] The present disclosure also provides compositions comprising any one or more of the inhibitory nucleic acid molecules. In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the compositions comprise a carrier and / or excipient. Examples of carriers include, but are not limited to, poly(lactic acid) (PLA) microspheres, poly(D,L-lactic-coglycolic-acid) (PLGA) microspheres, liposomes, micelles, inverse micelles, lipid cochleates, and lipid microtubules. A carrier may comprise a buffered salt solution such as PBS, HBSS, etc.

[0103] In some embodiments, the APOC3 inhibitor comprises compounds for carrying out gene editing. In some embodiments, the APOC3 inhibitor comprises a nuclease agent that induces one or more nicks or double-strand breaks at a recognition sequence(s) or a DNA- binding protein that binds to a recognition sequence within an APOC3 genomic nucleic acid molecule. The recognition sequence can be located within a coding region of the APOC3 gene, or within regulatory regions that influence the expression of the gene. A recognition sequence of the DNA-binding protein or nuclease agent can be located in an intron, an exon, a promoter, an enhancer, a regulatory region, or any non-protein coding region. The recognition sequence can include or be proximate to the start codon of the APOC3 gene. For example, the recognition sequence can be located about 10, about 20, about 30, about 40, about 50, about 100, about 200, about 300, about 400, about 500, or about 1,000 nucleotides from the start codon. As another example, two or more nuclease agents can be used, each targeting a nuclease recognition sequence including or proximate to the start codon. As another example, two nuclease agents can be used, one targeting a nuclease recognition sequence including or proximate to the start codon, and one targeting a nuclease recognition sequence including or proximate to the stop codon, wherein cleavage by the nuclease agents can result in deletion of the coding region between the two nuclease recognition sequences. Any nuclease agent that induces a nick or double-strand break into a desired recognition sequence can be used in the methods and compositions disclosed herein. Any DNA-binding protein that binds to a desired recognition sequence can be used in the methods and compositions disclosed herein.

[0104] Suitable nuclease agents and DNA-binding proteins for use herein include, but are not limited to, zinc finger protein or zinc finger nuclease (ZFN) pair, Transcription Activator-Like Effector (TALE) protein or Transcription Activator-Like Effector Nuclease (TALEN), or Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR) / CRISPR-associated (Cas) systems. The length of the recognition sequence can vary, and includes, for example, recognition sequences that are about 30-36 bp for a zinc finger protein or ZFN pair, about 15-18 bp for each ZFN, about 36 bp for a TALE protein or TALEN, and about 20 bp for a CRISPR / Cas guide RNA.

[0105] In some embodiments, CRISPR / Cas systems can be used to modify an APOC3 genomic nucleic acid molecule within a cell. The methods and compositions disclosed herein can employ CRISPR-Cas systems by utilizing CRISPR complexes (comprising a guide RNA (gRNA) complexed with a Cas protein) for site-directed cleavage of APOC3 nucleic acid molecules.

[0106] Cas proteins generally comprise at least one RNA recognition or binding domain that can interact with gRNAs. Cas proteins can also comprise nuclease domains (such as, for example, DNase or RNase domains), DNA binding domains, helicase domains, protein-protein interaction domains, dimerization domains, and other domains. Suitable Cas proteins include, for example, a wild type Cas9 protein and a wild type Cpfl protein (such as, for example, FnCpfl). A Cas protein can have full cleavage activity to create a double-strand break in an APOC3 genomic nucleic acid molecule, a PCSK9 genomic nucleic acid molecule, and / or an LPA genomic nucleic acid molecule, or it can be a nickase that creates a single-strand break in an APOC3 genomic nucleic acid molecule, a PCSK9 genomic nucleic acid molecule, and / or an LPA genomic nucleic acid molecule. Additional examples of Cas proteins include, but are not limited to, Casl, CaslB, Cas2, Cas3, Cas4, Cas5, Cas5e (CasD), Cas6, Cas6e, Cas6f, Cas7, Cas8al, Cas8a2, Cas8b, Cas8c, Cas9 (Csnl or Csxl2), CaslO, CaslOd, CasF, CasG, CasH, Csyl, Csy2, Csy3, Csel (CasA), Cse2 (CasB), Cse3 (CasE), Cse4 (CasC), Cscl, Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, Csm5, Csm6, Cmrl , Cmr3, Cmr4, Cmr5, Cmr6, Csbl, Csb2, Csb3, Csxl7, Csxl4, CsxlO, Csxl6, CsaX, Csx3, Csxl, Csxl5, Csfl, Csf2, Csf3, Csf4, and Cul966, and homologs or modified versions thereof. In some embodiments, a Cas system, such as Casl2a, can have multiple gRNAs encoded into a single crRNA. Cas proteins can also be operably linked to heterologous polypeptides as fusion proteins. For example, a Cas protein can be fused to a cleavage domain, an epigenetic modification domain, a transcriptional activation domain, or a transcriptional repressor domain. Cas proteins can be provided in any form. For example, a Cas protein can be provided in the form of a protein, such as a Cas protein complexed with a gRNA. Alternately, a Cas protein can be provided in the form of a nucleic acid molecule encoding the Cas protein, such as an RNA or DNA.

[0107] In some embodiments, targeted genetic modifications of APOC3 genomic nucleic acid molecules, PCSK9 genomic nucleic acid molecules, and / or LPA genomic nucleic acid molecules can be generated by contacting a cell with a Cas protein and one or more gRNAs that hybridize to one or more gRNA recognition sequences within a target genomic locus in the APOC3 genomic nucleic acid molecule, the PCSK9 genomic nucleic acid molecule, and / or the LPA genomic nucleic acid molecule. The gRNA recognition sequence can include or be proximate to the start codon of an APOC3 genomic nucleic acid molecule, a PCSK9 genomic nucleic acid molecule, and / or an LPA genomic nucleic acid molecule or the stop codon of an APOC3 genomic nucleic acid molecule, a PCSK9 genomic nucleic acid molecule, and / or an LPA genomic nucleic acid molecule. For example, the gRNA recognition sequence can be located from about 10, from about 20, from about 30, from about 40, from about 50, from about 100, from about 200, from about 300, from about 400, from about 500, or from about 1,000 nucleotides of the start codon or the stop codon. The gRNA recognition sequences within a target genomic locus in an APOC3 genomic nucleic acid molecule, a PCSK9 genomic nucleic acid molecule, and / or an LPA genomic nucleic acid molecule are located near a Protospacer Adjacent Motif (PAM) sequence, which is a 2-6 base pair DNA sequence immediately following the DNA sequence targeted by the Cas9 nuclease. The canonical PAM is the sequence 5'-NGG-3' where "N" is any nucleobase followed by two guanine ("G") nucleobases. gRNAs can transport Cas9 to anywhere in the genome for gene editing, but no editing can occur at any site other than one at which Cas9 recognizes PAM. In addition, 5'-NGA-3' can be a highly efficient non-canonical PAM for human cells. Generally, the PAM is about 2-6 nucleotides downstream of the DNA sequence targeted by the gRNA. The PAM can flank the gRNA recognition sequence. In some embodiments, the gRNA recognition sequence can be flanked on the 3' end by the PAM. In some embodiments, the gRNA recognition sequence can be flanked on the 5' end by the PAM. For example, the cleavage site of Cas proteins can be about 1 to about 10, about 2 to about 5 base pairs, or three base pairs upstream or downstream of the PAM sequence. In some embodiments (such as when Cas9 from S. pyogenes or a closely related Cas9 is used), the PAM sequence of the non- complementary strand can be 5'-NGG-3', where N is any DNA nucleotide and is immediately 3' of the gRNA recognition sequence of the non-complementary strand of the target DNA. As such, the PAM sequence of the complementary strand would be 5'-CCN-3', where N is any DNA nucleotide and is immediately 5' of the gRNA recognition sequence of the complementary strand of the target DNA.

[0108] A gRNA is an RNA molecule that binds to a Cas protein and targets the Cas protein to a specific location within an APOC3 genomic nucleic acid molecule, a PCSK9 genomic nucleic acid molecule, and / or an LPA genomic nucleic acid molecule. An exemplary gRNA is a gRNA effective to direct a Cas enzyme to bind to or cleave an APOC3 genomic nucleic acid molecule, a PCSK9 genomic nucleic acid molecule, and / or an LPA genomic nucleic acid molecule, wherein the gRNA comprises a DNA-targeting segment that hybridizes to a gRNA recognition sequence within the APOC3 genomic nucleic acid molecule, a PCSK9 genomic nucleic acid molecule, and / or an LPA genomic nucleic acid molecule. Exemplary gRNAs comprise a DNA-targeting segment that hybridizes to a gRNA recognition sequence present within an APOC3 genomic nucleic acid molecule, a PCSK9 genomic nucleic acid molecule, and / or an LPA genomic nucleic acid molecule that includes or is proximate to the start codon or the stop codon. For example, a gRNA can be selected such that it hybridizes to a gRNA recognition sequence that is located from about 5, from about 10, from about 15, from about 20, from about 25, from about 30, from about 35, from about 40, from about 45, from about 50, from about 100, from about 200, from about 300, from about 400, from about 500, or from about 1,000 nucleotides of the start codon or located from about 5, from about 10, from about 15, from about 20, from about 25, from about 30, from about 35, from about 40, from about 45, from about 50, from about 100, from about 200, from about 300, from about 400, from about 500, or from about 1,000 nucleotides of the stop codon. Suitable gRNAs can comprise from about 17 to about 25 nucleotides, from about 17 to about 23 nucleotides, from about 18 to about 22 nucleotides, or from about 19 to about 21 nucleotides. In some embodiments, the gRNAs can comprise 20 nucleotides.

[0109] The Cas protein and the gRNA form a complex, and the Cas protein cleaves the APOC3 genomic nucleic acid molecule, the PCSK9 genomic nucleic acid molecule, and / or the LPA genomic nucleic acid molecule. The Cas protein can cleave the nucleic acid molecule at a site within or outside of the nucleic acid sequence present in the APOC3 genomic nucleic acid molecule, the PCSK9 genomic nucleic acid molecule, and / or the LPA genomic nucleic acid molecule to which the DNA-targeting segment of a gRNA will bind. For example, formation of a CRISPR complex (comprising a gRNA hybridized to a gRNA recognition sequence and complexed with a Cas protein) can result in cleavage of one or both strands in or near (such as, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, or more base pairs from) the nucleic acid sequence present in the APOC3 genomic nucleic acid molecule, a PCSK9 genomic nucleic acid molecule, and / or an LPA genomic nucleic acid molecule to which a DNA-targeting segment of a gRNA will bind.

[0110] Such methods can result, for example, in an APOC3 genomic nucleic acid molecule, a PCSK9 genomic nucleic acid molecule, and / or an LPA genomic nucleic acid molecule in which a region of the APOC3 genomic nucleic acid molecule, the PCSK9 genomic nucleic acid molecule, and / or the LPA genomic nucleic acid molecule is disrupted, the start codon is disrupted, the stop codon is disrupted, or the coding sequence is disrupted or deleted. Optionally, the cell can be further contacted with one or more additional gRNAs that hybridize to additional gRNA recognition sequences within the target genomic locus in the APOC3 genomic nucleic acid molecule, the PCSK9 genomic nucleic acid molecule, and / or the LPA genomic nucleic acid molecule. By contacting the cell with one or more additional gRNAs (such as, for example, a second gRNA that hybridizes to a second gRNA recognition sequence), cleavage by the Cas protein can create two or more double-strand breaks or two or more single-strand breaks. The compounds described herein can be used in gene editing to replace a wild type allele of APOC3, CETP, LPA, and / or PCSK9 with any of the loss-of-function alleles described herein (or no replacement) in reference and heterozygous subjects.

[0111] In any of the methods of treatment or prevention described herein, the subject being treated may comprise an APOC3 variant nucleic acid molecule. In some embodiments, the subject being treated is heterozygous for the APOC3 variant nucleic acid molecule. In some embodiments, the subject being treated is homozygous for the APOC3 variant nucleic acid molecule. In some embodiments, the subject being treated is APOC3 reference. The APOC3 variant nucleic acid molecule can be any of the APOC3 variant nucleic acid molecules disclosed herein. In some embodiments, the APOC3 variant nucleic acid molecule is an APOC3 variant genomic nucleic acid molecule that comprises one or more of the genetic variations ll:116830491:A:T, ll:116830530:T:C, ll:116830568:A:G, ll:116830616:C:CT, ll:116830637:C:T, ll:116830638:G:A, ll:116830897:G:T, 11:116832769:G:A, ll:116832770:G:A, 11:116832882:T:G, ll:116830535:AC:A, ll:116830897:G:A, ll:116830898:T:A, 11:116832768:TG:T, 11:116832882:T:A, ll:116830491:A:C, ll:116830531:G:T, ll:116830542:GT:G, ll:116830584:T:C, ll:116830584:T:G, ll:116830638:G:T, ll:116830771:A:G, ll:116830868:C:T, ll:116830886:C:T, ll:116832805:G:A, 11:116832879:GCCTGAGA:G, ll:116830772:G:T, and 11:116832799:AC:A, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0112] In some embodiments, the methods of treatment or prevention further comprise detecting the presence or absence of an APOC3 variant nucleic acid molecule in a biological sample from the subject. In some embodiments, the APOC3 variant nucleic acid molecule can be any of the APOC3 variant nucleic acid molecules disclosed herein. In some embodiments, the APOC3 variant nucleic acid molecule is an APOC3 variant genomic nucleic acid molecule that comprises one or more of the genetic variations ll:116830491:A:T, ll:116830530:T:C, ll:116830568:A:G, ll:116830616:C:CT, ll:116830637:C:T, ll:116830638:G:A, ll:116830897:G:T, 11:116832769:G:A, ll:116832770:G:A, 11:116832882:T:G, ll:116830535:AC:A, ll:116830897:G:A, ll:116830898:T:A, 11:116832768:TG:T, 11:116832882:T:A, ll:116830491:A:C, ll:116830531:G:T, ll:116830542:GT:G, ll:116830584:T:C, ll:116830584:T:G, ll:116830638:G:T, ll:116830771:A:G,

[0113] 11:116830868:0:1, ll:116830886:C:T, ll:116832805:G:A, 11:116832879:GCCTGAGA:G, ll:116830772:G:T, and 11:116832799:AC:A, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0114] In some embodiments, the methods of treatment or prevention further comprise detecting the presence or absence of a PCSK9 variant nucleic acid molecule in a biological sample from the subject. In some embodiments, the PCSK9 variant nucleic acid molecule can be any of the PCSK9 variant nucleic acid molecules disclosed herein. In some embodiments, the PCSK9 variant nucleic acid molecule is a PCSK9 variant genomic nucleic acid molecule that comprises one or more of the genetic variations disclosed herein, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0115] In some embodiments, the methods of treatment or prevention further comprise detecting the presence or absence of an LPA variant nucleic acid molecule in a biological sample from the subject. In some embodiments, the LPA variant nucleic acid molecule can be any of the LPA variant nucleic acid molecules disclosed herein. In some embodiments, the LPA variant nucleic acid molecule is an LPA variant genomic nucleic acid molecule that comprises one or more of the genetic variations disclosed herein, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0116] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, by administering an aneurysm therapeutic agent or an aneurysm therapy, wherein the subject has an aneurysm or is at risk of developing an aneurysm. The methods comprise determining whether the subject has an APOC3 variant nucleic acid molecule by obtaining or having obtained a biological sample from the subject, and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the APOC3 variant nucleic acid molecule. In embodiments where the subject is APOC3 reference, the methods further comprise administering or continuing to administer the aneurysm therapeutic agent in an amount that is the same as or less than a standard dosage amount or an aneurysm therapy to the subject, and / or administering an APOC3 inhibitor to the subject. In embodiments where the subject is heterozygous for the APOC3 variant nucleic acid molecule, the methods further comprise administering or continuing to administer the aneurysm therapeutic agent in an amount that is the same as or less than a standard dosage amount or an aneurysm therapy to the subject, and / or administering an APOC3 inhibitor to the subject. In embodiments where the subject is homozygous for the APOC3 variant nucleic acid molecule, the methods further comprise administering or continuing to administer the aneurysm therapeutic agent in a standard dosage amount or an aneurysm therapy to the subject. The presence of an APOC3 variant nucleic acid molecule indicates the subject has a decreased risk of developing an aneurysm. In some embodiments, the subject is APOC3 reference. In some embodiments, the subject is heterozygous for an APOC3 variant nucleic acid molecule. In some embodiments, the subject is homozygous for an APOC3 variant nucleic acid molecule. In any of the embodiments described herein, the APOC3 inhibitor is an example of an aneurysm therapeutic agent. In some embodiments, the APOC3 variant nucleic acid molecule is an APOC3 variant genomic nucleic acid molecule that comprises one or more of the genetic variations ll:116830491:A:T, ll:116830530:T:C, ll:116830568:A:G, ll:116830616:C:CT, ll:116830637:C:T, ll:116830638:G:A, ll:116830897:G:T, 11:116832769:G:A, ll:116832770:G:A, 11:116832882:T:G, ll:116830535:AC:A, ll:116830897:G:A, ll:116830898:T:A,

[0117] 11:116832768:TG:T, 11:116832882:T:A, ll:116830491:A:C, ll:116830531:G:T, ll:116830542:GT:G, ll:116830584:T:C, ll:116830584:T:G, ll:116830638:G:T, ll:116830771:A:G, ll:116830868:C:T, ll:116830886:C:T, ll:116832805:G:A, 11:116832879:GCCTGAGA:G, ll:116830772:G:T, and 11:116832799:AC:A, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0118] For subjects that are genotyped or determined to be either APOC3 reference or heterozygous for an APOC3 variant nucleic acid molecule, such subjects can be administered an APOC3 inhibitor, as described herein.

[0119] In any of the embodiments described herein wherein an APOC3 inhibitor is administered to a subject, the subject can also be administered an LPA inhibitor.

[0120] Detecting the presence or absence of an APOC3 variant nucleic acid molecule in a biological sample from a subject and / or determining whether a subject has an APOC3 variant nucleic acid molecule can be carried out by any of the methods described herein. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the nucleic acid molecule can be present within a cell obtained from the subject. In some embodiments, when the subject is APOC3 reference, the subject is administered an aneurysm therapeutic agent in an amount that is the same as or less than a standard dosage amount or an aneurysm therapy, and / or an APOC3 inhibitor. In some embodiments, when the subject is heterozygous for an APOC3 variant nucleic acid molecule, the subject is administered an aneurysm therapeutic agent in an amount that is the same as or less than a standard dosage amount or an aneurysm therapy, and / or an APOC3 inhibitor.

[0121] In some embodiments, the treatment or prevention methods comprise detecting the presence or absence of a decrease in the expression of an APOC3 variant mRNA or polypeptide in a biological sample from the subject. In some embodiments, when the subject does not have a decrease in the expression of an APOC3 variant mRNA or polypeptide, the subject is administered an aneurysm therapeutic agent in an amount that is the same as or less than a standard dosage amount or an aneurysm therapy, and / or an APOC3 inhibitor. In some embodiments, when the subject has a decrease in the expression of an APOC3 variant mRNA or polypeptide, the subject is administered an aneurysm therapeutic agent in a standard dosage amount or an aneurysm therapy.

[0122] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, by administering an aneurysm therapeutic agent or an aneurysm therapy, wherein the subject has an aneurysm or is at risk of developing an aneurysm. The methods comprise determining whether the subject has a decrease in the expression of an APOC3 variant mRNA or polypeptide by obtaining or having obtained a biological sample from the subject, and performing or having performed an assay on the biological sample to determine if the subject a decrease in the expression of an APOC3 variant mRNA or polypeptide. In embodiments where the subject does not have a decrease in the expression of an APOC3 variant mRNA or polypeptide, the methods further comprise administering or continuing to administer the aneurysm therapeutic agent in an amount that is the same as or less than a standard dosage amount or an aneurysm therapy to the subject, and / or administering an APOC3 inhibitor to the subject. In embodiments where the subject has a decrease in the expression of an APOC3 variant mRNA or polypeptide, the methods further comprise administering or continuing to administer the aneurysm therapeutic agent in a standard dosage amount or an aneurysm therapy to the subject. The presence of a decrease in the expression of an APOC3 variant mRNA or polypeptide indicates the subject has a decreased risk of developing aneurysms. In some embodiments, the subject has a decrease in the expression of an APOC3 variant mRNA or polypeptide. In some embodiments, the subject does not have a decrease in the expression of an APOC3 variant mRNA or polypeptide. In any of the embodiments described herein, the APOC3 inhibitor is an example of an aneurysm therapeutic agent. In some embodiments, the APOC3 variant nucleic acid molecule is an APOC3 variant genomic nucleic acid molecule that comprises one or more of the genetic variations ll:116830491:A:T, ll:116830530:T:C, ll:116830568:A:G, ll:116830616:C:CT, ll:116830637:C:T, ll:116830638:G:A, ll:116830897:G:T, 11:116832769:G:A, ll:116832770:G:A, 11:116832882:T:G, ll:116830535:AC:A, ll:116830897:G:A, ll:116830898:T:A, 11:116832768:TG:T, 11:116832882:T:A, ll:116830491:A:C, ll:116830531:G:T, ll:116830542:GT:G, ll:116830584:T:C, ll:116830584:T:G, ll:116830638:G:T, ll:116830771:A:G, ll:116830868:C:T, ll:116830886:C:T, ll:116832805:G:A, 11:116832879:GCCTGAGA:G, ll:116830772:G:T, and 11:116832799:AC:A, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule. The APOC3 inhibitor can be an inhibitory nucleic acid molecule (e.g., antisense, siRNA, shRNA), a small molecule, an antibody, or compound(s) for gene editing.

[0123] Detecting a decrease in the expression of an APOC3 variant mRNA or polypeptide can be carried out by a variety of known methods. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the mRNA or polypeptide can be present within a cell obtained from the subject.

[0124] In some embodiments, the treatment or prevention methods comprise detecting the presence or absence of an APOC3 variant polypeptide in a biological sample from the subject. In some embodiments, when the subject does not have an APOC3 variant polypeptide, the subject is administered an aneurysm therapeutic agent in an amount that is the same as or less than a standard dosage amount or an aneurysm therapy, and / or an APOC3 inhibitor. In some embodiments, when the subject has an APOC3 variant polypeptide, the subject is administered an aneurysm therapeutic agent in standard dosage amount or an aneurysm therapy.

[0125] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, by administering an aneurysm therapeutic agent or an aneurysm therapy, wherein the subject has an aneurysm or is at risk of developing an aneurysm. The methods comprise determining whether the subject has an APOC3 variant polypeptide by obtaining or having obtained a biological sample from the subject and performing or having performed an assay on the biological sample to determine if the subject has an APOC3 variant polypeptide. When the subject does not have an APOC3 variant polypeptide, the subject is administered the aneurysm therapeutic agent in an amount that is the same as or less than a standard dosage amount or an aneurysm therapy, and / or an APOC3 inhibitor. When the subject has an APOC3 variant polypeptide, the subject is administered the aneurysm therapeutic agent in a standard dosage amount or an aneurysm therapy. The presence of an APOC3 variant polypeptide indicates the subject has a decreased risk of developing aneurysms. In some embodiments, the subject has an APOC3 variant polypeptide. In some embodiments, the subject does not have an APOC3 variant polypeptide.

[0126] The present disclosure also provides methods of preventing a subject from developing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, by administering an aneurysm therapeutic agent or aneurysm therapy that prevents aneurysms. In some embodiments, the method comprises determining whether the subject has an APOC3 variant polypeptide by obtaining or having obtained a biological sample from the subject and performing or having performed an assay on the biological sample to determine if the subject has an APOC3 variant polypeptide. When the subject does not have an APOC3 variant polypeptide, the subject is administered the aneurysm therapeutic agent in an amount that is the same as or less than a standard dosage amount or an aneurysm therapy, and / or an APOC3 inhibitor. When the subject has an APOC3 variant polypeptide, the subject is administered the aneurysm therapeutic agent in a standard dosage amount or an aneurysm therapy. The presence of an APOC3 variant polypeptide indicates the subject has a decreased risk of developing aneurysms. In some embodiments, the subject has an APOC3 variant polypeptide. In some embodiments, the subject does not have an APOC3 variant polypeptide.

[0127] Detecting the presence or absence of an APOC3 variant polypeptide in a biological sample from a subject and / or determining whether a subject has an APOC3 variant polypeptide can be carried out by any of the methods described herein. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the polypeptide can be present within a cell obtained from the subject. In some embodiments, the APOC3 inhibitor is a small molecule. In some embodiments, the small molecule is low molecular weight (< 900 daltons) organic compound.

[0128] In some embodiments, the APOC3 inhibitor comprises an antibody, or antigen-binding fragment thereof. In some embodiments, the antibody, or antigen-binding fragment thereof, binds specifically to human APOC3. In some embodiments, the antibody is a fully human monoclonal antibody (mAb), or antigen-binding fragment thereof, that specifically binds and neutralizes, inhibits, blocks, abrogates, reduces, or interferes with, at least one activity of APOC3, in particular, human APOC3. In some embodiments, an antibody or fragment thereof can neutralize, inhibit, block, abrogate, reduce, or interfere with, an activity of APOC3 by binding to an epitope of APOC3 that is directly involved in the targeted activity of APOC3. In some embodiments, an antibody or fragment thereof can neutralize, inhibit, block, abrogate, reduce, or interfere with, an activity of APOC3 by binding to an epitope of APOC3 that is not directly involved in the targeted activity of APOC3, but the antibody or fragment binding thereto sterically or conformationally inhibits, blocks, abrogates, reduces, or interferes with, the targeted activity of APOC3. In some embodiments, an antibody or fragment thereof binds to an epitope of APOC3 that is not directly involved in the targeted activity of APOC3 (i.e., a non-blocking antibody), but the antibody or fragment binding thereto results in the enhancement of the clearance of APOC3 from the circulation, compared to the clearance of APOC3 in the absence of the antibody or fragment thereof, thereby indirectly inhibiting, blocking, abrogating, reducing, or interfering with, an activity of APOC3. Clearance of APOC3 from the circulation can be particularly enhanced by combining two or more different nonblocking antibodies that do not compete with one another for specific binding to APOC3. The antibodies can be full-length (for example, an IgGl or lgG4 antibody) or may comprise only an antigen-binding portion (for example, a Fab, F(ab')z or scFv fragment), and may be modified to affect functionality, e.g., to eliminate residual effector functions (Reddy et al., J. Immunol., 2000, 164, 1925-1933).

[0129] In some embodiments, the antibody or antigen-binding fragment thereof specifically binds to APOC3 with an equilibrium dissociation constant ( KD) of about 7 nM or less, about 6 nM or less, about 5 nM or less, about 4 nM or less, about 3 nM or less, about 2 nM or less, or about 1 nM or less, as measured by surface plasmon resonance assay (for example, BIACORE™). In some embodiments, the antibody exhibits a KD of about 800 pM or less, about 700 pM or less; about 600 pM or less; about 500 pM or less; about 400 pM or less; about 300 pM or less; about 200 pM or less; about 100 pM or less; or about 50 pM or less.

[0130] In some embodiments, the anti-APOC3 antibodies have a modified glycosylation pattern. In some applications, modification to remove undesirable glycosylation sites may be useful, or e.g., removal of a fucose moiety to increase antibody dependent cellular cytotoxicity (ADCC) function (see, Shield et al., J. Biol. Chem., 2002, 277, 26733). In other applications, removal of N-glycosylation site may reduce undesirable immune reactions against the therapeutic antibodies or increase affinities of the antibodies. In yet other applications, modification of galactosylation can be made in order to modify complement dependent cytotoxicity (CDC).

[0131] The present disclosure also provides compositions comprising a combination of an antibody or antigen-binding fragment thereof and an aneurysm therapeutic agent.

[0132] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, by performing gene editing. The methods comprise determining whether the subject has an APOC3 variant nucleic acid molecule by obtaining or having obtained a biological sample from the subject, and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the APOC3 variant nucleic acid molecule. In embodiments where the subject is APOC3 reference or heterozygous for the APOC3 variant nucleic acid molecule, the methods further comprise performing or having performed gene editing on a subject to replace the reference copy of the APOC3 gene with an APOC3 variant nucleic acid molecule. The lack of an APOC3 variant nucleic acid molecule indicates the subject has an increased risk of developing an aneurysm. In some embodiments, the subject is APOC3 reference. In some embodiments, the subject is heterozygous for an APOC3 variant nucleic acid molecule. In some embodiments, the APOC3 variant nucleic acid molecule is an APOC3 variant genomic nucleic acid molecule that comprises one or more of the genetic variations disclosed herein, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0133] Detecting the presence or absence of an APOC3 variant nucleic acid molecule in a biological sample from a subject and / or determining whether a subject has an APOC3 variant nucleic acid molecule can be carried out by any of the methods described herein. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the nucleic acid molecule can be present within a cell obtained from the subject.

[0134] In some embodiments, the treatment or prevention methods comprise detecting the presence or absence of a decrease in the expression of an APOC3 variant mRNA or polypeptide in a biological sample from the subject. In some embodiments, when the subject does not have a decrease in the expression of an APOC3 variant mRNA or polypeptide, the subject is a candidate for gene editing.

[0135] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, by performing gene editing. The methods comprise determining whether the subject has a decrease in the expression of an APOC3 variant mRNA or polypeptide by obtaining or having obtained a biological sample from the subject, and performing or having performed an assay on the biological sample to determine if the subject a decrease in the expression of an APOC3 variant mRNA or polypeptide. In embodiments where the subject does not have a decrease in the expression of an APOC3 variant mRNA or polypeptide, the methods further comprise performing or having performed gene editing on a subject to replace the reference copy of the APOC3 gene with an APOC3 variant nucleic acid molecule. In some embodiments, the APOC3 variant nucleic acid molecule is an APOC3 variant genomic nucleic acid molecule that comprises one or more of the genetic variations disclosed herein, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0136] Detecting a decrease in the expression of an APOC3 variant mRNA or polypeptide can be carried out by a variety of known methods. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the mRNA or polypeptide can be present within a cell obtained from the subject.

[0137] In some embodiments, the treatment or prevention methods comprise detecting the presence or absence of an APOC3 variant polypeptide in a biological sample from the subject. In some embodiments, when the subject does not have an APOC3 variant polypeptide, the subject is a candidate for gene editing. The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, by performing gene editing. The methods comprise determining whether the subject has an APOC3 variant polypeptide by obtaining or having obtained a biological sample from the subject and performing or having performed an assay on the biological sample to determine if the subject has an APOC3 variant polypeptide. When the subject does not have an APOC3 variant polypeptide, the subject is a candidate for gene editing. The lack of an APOC3 variant polypeptide indicates the subject has an increased risk of developing aneurysms.

[0138] The present disclosure also provides methods of preventing a subject from developing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, by performing gene editing. In some embodiments, the method comprises determining whether the subject has an APOC3 variant polypeptide by obtaining or having obtained a biological sample from the subject and performing or having performed an assay on the biological sample to determine if the subject has an APOC3 variant polypeptide. When the subject does not have an APOC3 variant polypeptide, the subject is a candidate for gene editing. The lack of an APOC3 variant polypeptide indicates the subject has an increased risk of developing aneurysms.

[0139] Detecting the presence or absence of an APOC3 variant polypeptide in a biological sample from a subject and / or determining whether a subject has an APOC3 variant polypeptide can be carried out by any of the methods described herein. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the polypeptide can be present within a cell obtained from the subject.

[0140] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, by performing gene editing. The methods comprise determining whether the subject has a PCSK9 variant nucleic acid molecule by obtaining or having obtained a biological sample from the subject, and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the PCSK9 variant nucleic acid molecule. In embodiments where the subject is PCSK9 reference or heterozygous for the PCSK9 variant nucleic acid molecule, the methods further comprise performing or having performed gene editing on a subject to replace the reference copy of the PCSK9 gene with a PCSK9 variant nucleic acid molecule. The lack of a PCSK9 variant nucleic acid molecule indicates the subject has an increased risk of developing an aneurysm. In some embodiments, the subject is PCSK9 reference. In some embodiments, the subject is heterozygous for a PCSK9 variant nucleic acid molecule. In some embodiments, the PCSK9 variant nucleic acid molecule is a PCSK9 variant genomic nucleic acid molecule that comprises one or more of the genetic variations disclosed herein, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0141] Detecting the presence or absence of a PCSK9 variant nucleic acid molecule in a biological sample from a subject and / or determining whether a subject has a PCSK9 variant nucleic acid molecule can be carried out by any of the methods described herein. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the nucleic acid molecule can be present within a cell obtained from the subject.

[0142] In some embodiments, the treatment or prevention methods comprise detecting the presence or absence of a decrease in the expression of a PCSK9 variant mRNA or polypeptide in a biological sample from the subject. In some embodiments, when the subject does not have a decrease in the expression of a PCSK9 variant mRNA or polypeptide, the subject is a candidate for gene editing.

[0143] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, by performing gene editing. The methods comprise determining whether the subject has a decrease in the expression of a PCSK9 variant mRNA or polypeptide by obtaining or having obtained a biological sample from the subject, and performing or having performed an assay on the biological sample to determine if the subject a decrease in the expression of a PCSK9 variant mRNA or polypeptide. In embodiments where the subject does not have a decrease in the expression of a PCSK9 variant mRNA or polypeptide, the methods further comprise performing or having performed gene editing on a subject to replace the reference copy of the PCSK9 gene with the PCSK9 variant nucleic acid molecule. In some embodiments, the PCSK9 variant nucleic acid molecule is a PCSK9 variant genomic nucleic acid molecule that comprises one or more of the genetic variations disclosed herein, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0144] Detecting a decrease in the expression of a PCSK9 variant mRNA or polypeptide can be carried out by a variety of known methods. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the mRNA or polypeptide can be present within a cell obtained from the subject.

[0145] In some embodiments, the treatment or prevention methods comprise detecting the presence or absence of a PCSK9 variant polypeptide in a biological sample from the subject. In some embodiments, when the subject does not have a PCSK9 variant polypeptide, the subject is a candidate for gene editing.

[0146] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, by performing gene editing. The methods comprise determining whether the subject has a PCSK9 variant polypeptide by obtaining or having obtained a biological sample from the subject and performing or having performed an assay on the biological sample to determine if the subject has a PCSK9 variant polypeptide. When the subject does not have a PCSK9 variant polypeptide, the subject is a candidate for gene editing. The lack of a PCSK9 variant polypeptide indicates the subject has an increased risk of developing aneurysms.

[0147] The present disclosure also provides methods of preventing a subject from developing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, by performing gene editing. In some embodiments, the method comprises determining whether the subject has a PCSK9 variant polypeptide by obtaining or having obtained a biological sample from the subject and performing or having performed an assay on the biological sample to determine if the subject has a PCSK9 variant polypeptide. When the subject does not have a PCSK9 variant polypeptide, the subject is a candidate for gene editing. The lack of a PCSK9 variant polypeptide indicates the subject has an increased risk of developing aneurysms.

[0148] Detecting the presence or absence of a PCSK9 variant polypeptide in a biological sample from a subject and / or determining whether a subject has a PCSK9 variant polypeptide can be carried out by any of the methods described herein. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the polypeptide can be present within a cell obtained from the subject.

[0149] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, by performing gene editing. The methods comprise determining whether the subject has an LPA variant nucleic acid molecule by obtaining or having obtained a biological sample from the subject, and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the LPA variant nucleic acid molecule. In embodiments where the subject is heterozygous or homozygous for the LPA variant nucleic acid molecule, the methods further comprise performing or having performed gene editing on a subject to disrupt the LPA variant nucleic acid molecule. The presence of an LPA variant nucleic acid molecule indicates the subject has an increased risk of developing an aneurysm. In some embodiments, the subject is heterozygous for an LPA variant nucleic acid molecule. In some embodiments, the subject is homozygous for an LPA variant nucleic acid molecule. In some embodiments, the LPA variant nucleic acid molecule is an LPA variant genomic nucleic acid molecule that comprises one or more of the genetic variations disclosed herein, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0150] Detecting the presence or absence of an LPA variant nucleic acid molecule in a biological sample from a subject and / or determining whether a subject has an LPA variant nucleic acid molecule can be carried out by any of the methods described herein. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the nucleic acid molecule can be present within a cell obtained from the subject.

[0151] In some embodiments, the treatment or prevention methods comprise detecting the presence or absence of an increase in the expression of an LPA variant mRNA or polypeptide in a biological sample from the subject. In some embodiments, when the subject has an increase in the expression of an LPA variant mRNA or polypeptide, the subject is a candidate for gene editing. The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, by performing gene editing. The methods comprise determining whether the subject has an increase in the expression of an LPA variant mRNA or polypeptide by obtaining or having obtained a biological sample from the subject, and performing or having performed an assay on the biological sample to determine if the subject has an increase in the expression of an LPA variant mRNA or polypeptide. In embodiments where the subject has an increase in the expression of an LPA variant mRNA or polypeptide, the methods further comprise performing or having performed gene editing on a subject to disrupt the LPA variant nucleic acid molecule. In some embodiments, the LPA variant nucleic acid molecule is an LPA variant genomic nucleic acid molecule that comprises one or more of the genetic variations disclosed herein, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0152] Detecting an increase in the expression of an LPA variant mRNA or polypeptide can be carried out by a variety of known methods. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the mRNA or polypeptide can be present within a cell obtained from the subject.

[0153] In some embodiments, the treatment or prevention methods comprise detecting the presence or absence of an LPA variant polypeptide in a biological sample from the subject. In some embodiments, when the subject has an LPA variant polypeptide, the subject is a candidate for gene editing.

[0154] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, by performing gene editing. The methods comprise determining whether the subject has an LPA variant polypeptide by obtaining or having obtained a biological sample from the subject and performing or having performed an assay on the biological sample to determine if the subject has an LPA variant polypeptide. When the subject has an LPA variant polypeptide, the subject is a candidate for gene editing. The presence of an LPA variant polypeptide (having increased activity or expression) indicates the subject has an increased risk of developing aneurysms. The present disclosure also provides methods of preventing a subject from developing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, by performing gene editing. In some embodiments, the method comprises determining whether the subject has an LPA variant polypeptide by obtaining or having obtained a biological sample from the subject and performing or having performed an assay on the biological sample to determine if the subject has an LPA variant polypeptide. When the subject has an LPA variant polypeptide (having increased activity or expression), the subject is a candidate for gene editing. The presence of an LPA variant polypeptide indicates the subject has an increased risk of developing aneurysms.

[0155] Detecting the presence or absence of an LPA variant polypeptide in a biological sample from a subject and / or determining whether a subject has an LPA variant polypeptide can be carried out by any of the methods described herein. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the polypeptide can be present within a cell obtained from the subject.

[0156] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, the methods comprising performing gene editing to disrupt the LPA gene in the subject, wherein the subject comprises an Lp(a) level > 31 mg / dL. In some embodiments, the method further comprises detecting the amount of Lp(a) in a biological sample from the subject. Any of the biological samples described herein can be used.

[0157] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm. The methods comprise determining or having determined the level of Lp(a) in the subject. The level of Lp(a) can be determined by, for example, obtaining or having obtained a biological sample from the subject, and performing or having performed an assay on the biological sample to determine if the subject has an Lp(a) level > 31 mg / dL. The methods also comprise performing or having performed gene editing on a subject that has an Lp(a) level > 31 mg / dL to disrupt the LPA gene in the subject. An Lp(a) level > 31 mg / dL indicates the subject has an increased risk of developing an aneurysm. In some embodiments, the subject comprises an Lp(a) level > 31 mg / dL, > 35 mg / dL, > 40 mg / dL, > 45 mg / dL, > 50 mg / dL, > 55 mg / dL, > 60 mg / dL, > 65 mg / dL, > 70 mg / dL, > 75 mg / dL, > 80 mg / dL, > 85 mg / dL, > 90 mg / dL, > 95 mg / dL, or > 100 mg / dL.

[0158] Detecting the Lp(a) level in a biological sample from a subject can be carried out by any method known to the skilled artisan. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the polypeptide can be present within a cell obtained from the subject.

[0159] In some embodiments, the aneurysm is an abdominal aortic aneurysm, a thoracic aortic aneurysm, a cerebral aneurysm, a carotid aneurysm, a popliteal aneurysm, a mesenteric aneurysm, or a splenic aneurysm. In some embodiments, the aneurysm is an abdominal aortic aneurysm. In some embodiments, the subject is also administered an aneurysm therapeutic agent.

[0160] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, the methods comprising performing gene editing to disrupt the LPA gene in the subject, wherein the subject comprises an LPA polygenic risk score (PRS) (LPA PRS) that is greater than the 60% percentile. In some embodiments, the methods further comprise performing an LPA PRS for the subject.

[0161] The present disclosure also provides methods of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm. The methods comprise performing an LPA PRS for the subject. The methods also comprise performing gene editing to disrupt the LPA gene in the subject, wherein the subject comprises an LPA PRS that is greater than the 60% percentile. An LPA PRS that is greater than the 60% percentile indicates the subject has an increased risk of developing an aneurysm.

[0162] In some embodiments, the subject comprises an LPA PRS that is greater than the 60% percentile, greater than the 65% percentile, greater than the 70% percentile, greater than the 75% percentile, greater than the 80% percentile, greater than the 85% percentile, greater than the 90% percentile, or greater than the 95% percentile.

[0163] The present disclosure also provides methods of treating a subject having an abdominal aortic aneurysm or at risk of developing an abdominal aortic aneurysm, or preventing an abdominal aortic aneurysm, preventing progression of an abdominal aortic aneurysm, or preventing a complication of an abdominal aortic aneurysm, the methods comprising administering: a therapeutic agent that decreases low-density lipoprotein (LDL); and / or a therapeutic agent that increases high-density lipoprotein (HDL). In some embodiments, the method comprises administering a therapeutic agent that decreases LDL. In some embodiments, the method comprises administering a therapeutic agent that increases HDL. In some embodiments, the therapeutic agent that decreases LDL comprises a statin, a PCSK9 inhibitor, a fibrate, a bile acid resin, an omega-3 fatty acid, an adenosine triphosphate-or a citrate lyase (ACL) inhibitor, or any combination thereof. The PCSK9 inhibitor can be an inhibitory nucleic acid molecule (e.g., antisense, siRNA, shRNA), a small molecule, an antibody, or compound(s) for gene editing. Examples of PCSK9 inhibitors include, but are not limited to, alirocumab, evolocumab, inclisiran, and bococizumab, or any combination thereof. Examples of statins include, but are not limited to, atorvastatin, simvastatin, rosuvastatin, pravastatin, lovastatin, pitavastatin, and fluvastatin, or any combination thereof. Examples of fibrates include, but are not limited to, gemfibrozil, fenofibric acid, and clofibrate, or any combination thereof. An example of a bile acid resin is colesevelam. An example of an ACL inhibitor is bempedoic acid. Additional therapeutic agents include, but are not limited to, lomitapide, ezetimibe, delta / gamma tocotrienol, a phytosterol, nicotinic acid, any niacin, or any combination thereof. In some embodiments, the therapeutic agent that increases HDL comprises niacin, a fibrate, rosuvastatin, pitavastatin, or an omega-3 fatty acid, or any combination thereof.

[0164] In some embodiments, the method comprises administering a therapeutic agent that decreases LDL and does not comprise administering a therapeutic agent that increases HDL (i.e., the method comprises monotherapy with a therapeutic agent that decreases LDL). In such embodiments, the therapeutic agent that decreases LDL comprises a statin, a fibrate, a bile acid resin, an omega-3 fatty acid, an adenosine triphosphate-or an ACL inhibitor, or any combination thereof. In such embodiments, the therapeutic agent that decreases LDL does not comprise a PCSK9 inhibitor.

[0165] In any of the embodiments described herein, there exists a general therapeutic expectation of any modulator of HDL-C and LDL-C being protective against AAA, with dual modulation (i.e., lowering LDL-C and raising HDL-C) providing the strongest effect. Without being bound to any particular theory, in some embodiments, the modulator is effective to influence both HDL level and LDL level such as, but not limited to, APOC3 inhibitor or CETP inhibitor. In some embodiments, the modulator is effective to influence both LDL and Lp(a) level, and include, but is not limited to, for example, a PCSK9 inhibitor.

[0166] In some embodiments, the method comprises administering a PCSK9 inhibitor to the subject. The PCSK9 inhibitor can be an inhibitory nucleic acid molecule (e.g., antisense, siRNA, shRNA), a small molecule, an antibody, or compound(s) for gene editing. In some embodiments, the method comprises administering alirocumab, evolocumab, inclisiran, or bococizumab, or any combination thereof to the subject. In some embodiments, the method comprises administering alirocumab to the subject. In some embodiments, the method comprises administering a PCSK9 inhibitor and an APOC3 inhibitor to the subject. Without being bound to any particular theory, in some embodiments, the PCSK9 inhibitor is effective to modulate both LDL level and Lp(a) level, particularly in LPA high genetic risk score (e.g., LPA GRS top 33%).

[0167] In some embodiments, the method further comprises administering an APOC3 inhibitor to the subject. Any of the APOC3 inhibitors described herein can be used. In some embodiments, the APOC3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an APOC3 nucleic acid molecule. In some embodiments, the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, an siRNA, and / or an shRNA. In some embodiments, the inhibitory nucleic acid molecule comprises an siRNA. In some embodiments, the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule.

[0168] In some embodiments, the method further comprises administering a cholesteryl ester transfer protein (CETP) inhibitor to the subject. The CTEP inhibitor can be an inhibitory nucleic acid molecule (e.g., antisense, siRNA, shRNA), a small molecule, an antibody, or compound(s) for gene editing. In some embodiments, the CETP inhibitor comprises anacetrapib, obicetrapib, torcetrapib, dalcetrapib, or evacetrapib, or any combination thereof. In some embodiments, the CETP inhibitor comprises anacetrapib or obicetrapib, or a combination thereof.

[0169] The present disclosure also provides methods of treating a subject having an abdominal aortic aneurysm or at risk of developing an abdominal aortic aneurysm, or preventing an abdominal aortic aneurysm, preventing progression of an abdominal aortic aneurysm, or preventing a complication of an abdominal aortic aneurysm, the methods comprising administering a CETP inhibitor to the subject. The CTEP inhibitor can be an inhibitory nucleic acid molecule (e.g., antisense, siRNA, shRNA), a small molecule, an antibody, or compound(s) for gene editing. In some embodiments, the CETP inhibitor comprises anacetrapib, obicetrapib, torcetrapib, dalcetrapib, or evacetrapib, or any combination thereof. In some embodiments, the CETP inhibitor comprises anacetrapib or obicetrapib, or a combination thereof. In any of the methods described herein wherein a CETP inhibitor is administered to a subject, the subject can also be administered an APOC3 inhibitor. In any of the methods described herein wherein a CETP inhibitor is administered to a subject, the subject can also be administered an PCSK9 inhibitor. In any of the methods described herein wherein a CETP inhibitor is administered to a subject, the subject can also be administered an APOC3 inhibitor and a PCSK9 inhibitor.

[0170] The present disclosure also provides methods of treating a subject having an abdominal aortic aneurysm or at risk of developing an abdominal aortic aneurysm, or preventing an abdominal aortic aneurysm, preventing progression of an abdominal aortic aneurysm, or preventing a complication of an abdominal aortic aneurysm, the methods comprising administering: a PCSK9 inhibitor and an LPA inhibitor. In some embodiments, the methods further comprise administering a CETP inhibitorto the subject.

[0171] The present disclosure also provides therapeutic agents that decrease LDL and / or therapeutic agents that increase HDL for use in treating an abdominal aortic aneurysm, preventing an abdominal aortic aneurysm, preventing progression of an abdominal aortic aneurysm, or preventing a complication of an abdominal aortic aneurysm in a subject. In some embodiments, the therapeutic agent that decreases LDL comprises a statin, a PCSK9 inhibitor, a fibrate, a bile acid resin, an omega-3 fatty acid, an adenosine triphosphate-or a citrate lyase (ACL) inhibitor, or any combination thereof. Examples of statins include, but are not limited to, atorvastatin, simvastatin, rosuvastatin, pravastatin, lovastatin, pitavastatin, and fluvastatin, or any combination thereof. The PCSK9 inhibitor can be an inhibitory nucleic acid molecule (e.g., antisense, siRNA, shRNA), a small molecule, an antibody, or compound(s) for gene editing. Examples of PCSK9 inhibitors include, but are not limited to, alirocumab, evolocumab, inclisiran, and bococizumab, or any combination thereof. Examples of fibrates include, but are not limited to, gemfibrozil, fenofibric acid, and clofibrate, or any combination thereof. Examples of bile acid resins include, but are not limited to, colesevelam, cholestyramine, and colestipol, or any combination thereof. An example of an ACL inhibitor is bempedoic acid. Additional therapeutic agents include, but are not limited to, lomitapide, ezetimibe, delta / gamma tocotrienol, a phytosterol, nicotinic acid, any niacin, or any combination thereof. In some embodiments, the therapeutic agent that increases HDL comprises niacin, a fibrate, rosuvastatin, pitavastatin, or an omega-3 fatty acid, or any combination thereof.

[0172] The present disclosure also provides CETP inhibitors for use in treating an abdominal aortic aneurysm, preventing an abdominal aortic aneurysm, preventing progression of an abdominal aortic aneurysm, or preventing a complication of an abdominal aortic aneurysm in a subject. The CTEP inhibitor can be an inhibitory nucleic acid molecule (e.g., antisense, siRNA, shRNA), a small molecule, an antibody, or compound(s) for gene editing. In some embodiments, the CETP inhibitor comprises anacetrapib, obicetrapib, torcetrapib, dalcetrapib, or evacetrapib, or any combination thereof. In some embodiments, the CETP inhibitor comprises anacetrapib or obicetrapib, or a combination thereof.

[0173] In some embodiments, the aneurysm is an abdominal aortic aneurysm, a thoracic aortic aneurysm, a cerebral aneurysm, a carotid aneurysm, a popliteal aneurysm, a mesenteric aneurysm, or a splenic aneurysm. In some embodiments, the aneurysm is an abdominal aortic aneurysm. In some embodiments, the subject is also administered an aneurysm therapeutic agent.

[0174] In some embodiments, the aneurysm therapeutic agents include, but are not limited to, acetaminophen, a calcium channel blocker (such as, for example, verapamil and diltiazem), nimodipine, a vasodilator, levetiracetam, phenytoin, valproic acid, metoprolol, a beta blocker (such as, for example, metoprolol, esmolol, and labeta lol ), an angiotensin II receptor blocker, including losartan, valsartan, and olmesartan, a statin, including atorvastatin, lovastatin, simvastatin, a nitroprusside, an adrenergic modifier, an angiotensin-converting enzyme (ACE) inhibitor, a direct renin inhibitor, a direct vasodilator, and a diuretic. Additional aneurysm therapies include any therapy used to reduce or manage aneurysm risk factors. In some embodiments, the aneurysm therapeutic agent includes APOC3 inhibitors, PCSK9 inhibitors, and / or LPA inhibitors (gene inhibitor or protein inhibitor). In some embodiments, the aneurysm therapeutic agent or aneurysm therapy can be combined with an APOC3 inhibitor. In some embodiments, the aneurysm therapy is surgical clipping to close off an aneurysm, endovascular aortic aneurysm repair, flow diverter, an intraluminal flow disrupter, coiling, coiling in combination with stenting, different combinations of various devices to destroy the aneurysm from inside the blood vessel, open-chest surgery, aortic root surgery, angioplasty, ventricular or lumbar draining catheters, shunt surgery, rehabilitative therapy, exercise. These treatment therapies may be delayed or avoided altogether by treatment with an APOC3 inhibitor as described herein.

[0175] In some embodiments, the methods further comprise administering a cholesteryl ester transfer protein (CETP) inhibitor to the subject. The CTEP inhibitor can be an inhibitory nucleic acid molecule (e.g., antisense, siRNA, shRNA), a small molecule, an antibody, or compound(s) for gene editing. In some embodiments, the CETP inhibitor comprises anacetrapib, obicetrapib, torcetrapib, dalcetrapib, or evacetrapib, or any combination thereof. In some embodiments, the CETP inhibitor comprises anacetrapib or obicetrapib, or a combination thereof.

[0176] In some embodiments, the dose of the aneurysm therapeutic agents can be decreased by about 10%, by about 20%, by about 30%, by about 40%, by about 50%, by about 60%, by about 70%, by about 80%, or by about 90% for subjects that are heterozygous for an APOC3 variant nucleic acid molecule or APOC3 reference (i.e., a less than the standard dosage amount) compared to subjects that are homozygous for an APOC3 variant nucleic acid molecule (who may receive a standard dosage amount). In some embodiments, the dose of the aneurysm therapeutic agents can be decreased by about 10%, by about 20%, by about 30%, by about 40%, or by about 50%. In some embodiments, the dose of the aneurysm therapeutic agents can be decreased by about 10%, by about 20%, by about 30%, by about 40%, by about 50%, by about 60%, by about 70%, by about 80%, or by about 90% for subjects that are heterozygous for an APOC3 variant nucleic acid molecule or APOC3 reference compared to subjects that are APOC3 reference. In addition, subjects that are heterozygous for an APOC3 variant nucleic acid molecule or APOC3 reference can be administered the aneurysm therapeutic agents less frequently compared to subjects that are heterozygous for the APOC3 variant nucleic acid molecule.

[0177] Administration of the aneurysm therapeutic agents and / or APOC3 inhibitors and / or CTEP inhibitors can be repeated, for example, after one day, two days, three days, five days, one week, two weeks, three weeks, one month, five weeks, six weeks, seven weeks, eight weeks, two months, or three months. The repeated administration can be at the same dose or at a different dose. The administration can be repeated once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, or more. For example, according to certain dosage regimens a subject can receive therapy for a prolonged period of time such as, for example, 6 months, 1 year, or more. Administration of the aneurysm therapeutic agents and / or APOC3 inhibitors and / or CTEP inhibitors can occur by any suitable route including, but not limited to, parenteral, intravenous, oral, subcutaneous, intra-arterial, intracranial, intrathecal, intraperitoneal, topical, intranasal, or intramuscular. Pharmaceutical compositions for administration are desirably sterile and substantially isotonic and manufactured under GMP conditions. Pharmaceutical compositions can be provided in unit dosage form (i.e., the dosage for a single administration). Pharmaceutical compositions can be formulated using one or more physiologically and pharmaceutically acceptable carriers, diluents, excipients, or auxiliaries. The formulation depends on the route of administration chosen. The term "pharmaceutically acceptable" means that the carrier, diluent, excipient, or auxiliary is compatible with the other ingredients of the formulation and not substantially deleterious to the recipient thereof.

[0178] The terms "treat", "treating", and "treatment" and "prevent", "preventing", and "prevention" as used herein, refer to eliciting the desired biological response, such as a therapeutic and prophylactic effect, respectively. In some embodiments, a therapeutic effect comprises one or more of a decrease / reduction in aneurysms, a decrease / reduction in the severity of aneurysms (such as, for example, a reduction or inhibition of development of aneurysms), a decrease / reduction in symptoms and disease-related effects, delaying the onset of symptoms and disease-related effects, reducing the severity of symptoms of disease-related effects, reducing the number of symptoms and disease-related effects, reducing the latency of symptoms and disease-related effects, an amelioration of symptoms and disease-related effects, reducing secondary symptoms, reducing secondary infections, preventing relapse to aneurysms, decreasing the number or frequency of relapse episodes, increasing latency between symptomatic episodes, increasing time to sustained progression, speeding recovery, or increasing efficacy of or decreasing resistance to alternative therapeutics, and / or an increased survival time of the affected host animal, following administration of the agent or composition comprising the agent. A prophylactic effect may comprise a complete or partial avoidance / inhibition or a delay of aneurysm development / progression (such as, for example, a complete or partial avoidance / inhibition or a delay), and an increased survival time of the affected host animal, following administration of a therapeutic protocol. Treatment of aneurysms encompasses the treatment of a subject already diagnosed as having any form of aneurysm at any clinical stage or manifestation, the delay of the onset or evolution or aggravation or deterioration of the symptoms or signs of aneurysms, and / or preventing and / or reducing the severity of aneurysms.

[0179] In some embodiments, the methods of gene editing include, but are not limited to programmable nucleases (gene editing tools) such as zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), clustered regularly interspaced short palindromic repeats (CRISPR / Cas), base editing (BE; cytosine BE (CBE) / adenine BE (ABE)), and prime editing (PE) (see, Phan et al., Genes, 2023, 14, 1-21, which is incorporated herein by reference in its entirety). Suitable delivery systems include, but are not limited to, virus (AAV and lentivirus), and non-virus (silica nanoconstruct (SN), engineered virus like particle (eVLP), nanoparticle).

[0180] In some embodiments, the gene editing methods comprise a nuclease agent that induces one or more nicks or double-strand breaks at a recognition sequence(s) or a DNA- binding protein that binds to a recognition sequence within an APOC3 genomic nucleic acid molecule, a PCSK9 genomic nucleic acid molecule, and / or an LPA genomic nucleic acid molecule. The recognition sequence can be located within a coding region of the APOC3 gene, the PCSK9 gene, and / or the LPA gene, or within regulatory regions that influence the expression of the gene. A recognition sequence of the DNA-binding protein or nuclease agent can be located in an intron, an exon, a promoter, an enhancer, a regulatory region, or any nonprotein coding region. The recognition sequence can include or be proximate to the start codon of the APOC3 gene, the PCSK9 gene, and / or the LPA gene. For example, the recognition sequence can be located about 10, about 20, about 30, about 40, about 50, about 100, about 200, about 300, about 400, about 500, or about 1,000 nucleotides from the start codon. As another example, two or more nuclease agents can be used, each targeting a nuclease recognition sequence including or proximate to the start codon. As another example, two nuclease agents can be used, one targeting a nuclease recognition sequence including or proximate to the start codon, and one targeting a nuclease recognition sequence including or proximate to the stop codon, wherein cleavage by the nuclease agents can result in deletion of the coding region between the two nuclease recognition sequences. Any nuclease agent that induces a nick or double-strand break into a desired recognition sequence can be used in the methods and compositions disclosed herein. Any DNA-binding protein that binds to a desired recognition sequence can be used in the methods and compositions disclosed herein. Suitable nuclease agents and DNA-binding proteins for use herein include any of those described herein. In some embodiments, CRISPR / Cas systems can be used to modify an APOC3 genomic nucleic acid molecule, a PCSK9 genomic nucleic acid molecule, and / or an LPA genomic nucleic acid molecule within a cell. The methods and compositions disclosed herein can employ CRISPR-Cas systems by utilizing CRISPR complexes (comprising a guide RNA (gRNA) complexed with a Cas protein) for site-directed cleavage of APOC3 nucleic acid molecules, PCSK9 nucleic acid molecules, and / or LPA nucleic acid molecules. Cas proteins generally comprise at least one RNA recognition or binding domain that can interact with gRNAs as described herein.

[0181] The present disclosure also provides methods of identifying a subject having an increased risk of developing an aneurysm. In some embodiments, the method comprises determining or having determined in a biological sample obtained from the subject the presence or absence of an APOC3 variant nucleic acid molecule (such as a genomic nucleic acid molecule, mRNA molecule, and / or cDNA molecule). When the subject lacks an APOC3 variant nucleic acid molecule (i.e., the subject is genotypically categorized as APOC3 reference), then the subject has an increased risk of developing an aneurysm. When the subject has an APOC3 variant nucleic acid molecule (i.e., the subject is heterozygous or homozygous for an APOC3 variant nucleic acid molecule), then the subject has a decreased risk of developing an aneurysm. In some embodiments, the APOC3 variant nucleic acid molecule is an APOC3 variant genomic nucleic acid molecule that comprises one or more of the genetic variations ll:116830491:A:T, ll:116830530:T:C, ll:116830568:A:G, ll:116830616:C:CT, ll:116830637:C:T, ll:116830638:G:A, ll:116830897:G:T, 11:116832769:G:A, ll:116832770:G:A, 11:116832882:T:G, ll:116830535:AC:A, ll:116830897:G:A, ll:116830898:T:A, 11:116832768:TG:T, 11:116832882:T:A, ll:116830491:A:C, ll:116830531:G:T, ll:116830542:GT:G, ll:116830584:T:C, ll:116830584:T:G, ll:116830638:G:T, ll:116830771:A:G, ll:116830868:C:T, ll:116830886:C:T, ll:116832805:G:A, 11:116832879:GCCTGAGA:G, ll:116830772:G:T, and 11:116832799:AC:A, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0182] Having a single copy of an APOC3 variant nucleic acid molecule is more protective of a subject from developing an aneurysm than having no copies of an APOC3 variant nucleic acid molecule. Without intending to be limited to any particular theory or mechanism of action, it is believed that a single copy of an APOC3 variant nucleic acid molecule (i.e., heterozygous for an APOC3 variant nucleic acid molecule) is protective of a subject from developing an aneurysm and it is also believed that having two copies of an APOC3 variant nucleic acid molecule (i.e., homozygous for an APOC3 variant nucleic acid molecule) may be more protective of a subject from developing an aneurysm, relative to a subject with a single copy. Thus, in some embodiments, a single copy of an APOC3 variant nucleic acid molecule may not be completely protective, but instead, may be partially or incompletely protective of a subject from developing an aneurysm. While not desiring to be bound by any particular theory, there may be additional factors or molecules involved in the development of aneurysms that are still present in a subject having a single copy of an APOC3 variant nucleic acid molecule, thus resulting in less than complete protection from the development of aneurysms.

[0183] Determining whether a subject has an APOC3 variant nucleic acid molecule in a biological sample from a subject and / or determining whether a subject has an APOC3 variant nucleic acid molecule can be carried out by any of the methods described herein. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the nucleic acid molecule can be present within a cell obtained from the subject.

[0184] In some embodiments, when a subject is identified as having an increased risk of developing aneurysms, the subject is administered an aneurysm therapeutic agent or aneurysm therapy, and / or an APOC3 inhibitor, as described herein. For example, when the subject is APOC3 reference, and therefore has an increased risk of developing an aneurysm, the subject is administered an aneurysm therapeutic agent in an amount that is the same as or less than a standard dosage amount or an aneurysm therapy, and / or is administered an APOC3 inhibitor. In some embodiments, when the subject is heterozygous for an APOC3 variant nucleic acid molecule, the subject is administered the aneurysm therapeutic agent in an amount that is the same as or less than a standard dosage amount or an aneurysm therapy, and / or is administered an APOC3 inhibitor. In some embodiments, when the subject is homozygous for an APOC3 variant nucleic acid molecule, the subject is administered an aneurysm therapeutic agent in a standard dosage amount or an aneurysm therapy. In some embodiments, the subject is APOC3 reference. In some embodiments, the subject is heterozygous for an APOC3 variant nucleic acid molecule. In some embodiments, the subject is homozygous for an APOC3 variant nucleic acid molecule. The present disclosure also provides methods of determining a subject's aggregate burden, or risk score, of having two or more APOC3 variant nucleic acid molecules, and / or two or more APOC3 variant polypeptides associated with a decreased risk of developing aneurysms. The aggregate burden is the sum of two or more genetic variants that can be carried out in an association analysis with aneurysms. In some embodiments, the subject is homozygous for one or more APOC3 variant nucleic acid molecules associated with a decreased risk of developing aneurysms. In some embodiments, the subject is heterozygous for one or more APOC3 variant nucleic acid molecules associated with a decreased risk of developing aneurysms. When the subject has a lower aggregate burden, the subject has an increased risk of developing aneurysms, and the subject is administered or continued to be administered the aneurysm therapeutic agent in an amount that is the same as or less than the standard dosage amount or an aneurysm therapy, and / or an APOC3 inhibitor. When the subject has a higher aggregate burden, the subject has a decreased risk of developing an aneurysm and the subject is administered or continued to be administered the aneurysm therapeutic agent in a standard dosage amount or an aneurysm therapy. The higher the aggregate burden, the lower the risk of developing aneurysms.

[0185] In some embodiments, a subject's aggregate burden of having any two or more APOC3 variant nucleic acid molecules represents a weighted sum of a plurality of any of the APOC3 variant nucleic acid molecules. In some embodiments, the aggregate burden is calculated using at least about 2, at least about 3, at least about 4, at least about 5, at least about 10, at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 100, at least about 120, at least about 150, at least about 200, at least about 250, at least about 300, at least about 400, at least about 500, at least about 1,000, at least about 10,000, at least about 100,000, or at least about or more than 1,000,000 genetic variants present in or around (up to 10 Mb) the APOC3 gene, where the genetic burden is the number of alleles multiplied by the association estimate with aneurysms or related outcome for each allele (e.g., a weighted polygenic burden score). In some embodiments, when the subject has an aggregate burden higher than a desired threshold score, the subject has a decreased risk of developing an aneurysm. In some embodiments, when the subject has an aggregate burden lower than a desired threshold score, the subject has an increased risk of developing an aneurysm. In some embodiments, the APOC3 aggregate burden may be divided into quintiles, e.g., top quintile, second quintile, intermediate quintile, fourth quintile, and bottom quintile, wherein the top quintile of aggregate burden corresponds to the lowest risk group and the bottom quintile of aggregate burden corresponds to the highest risk group. In some embodiments, a subject having a higher aggregate burden comprises the highest weighted aggregate burdens, including, but not limited to the top 10%, top 20%, top 30%, top 40%, or top 50% of aggregate burdens from a subject population. In some embodiments, the genetic variants comprise the genetic variants having association with aneurysms in the top 10%, top 20%, top 30%, top 40%, or top 50% of p-value range for the association. In some embodiments, each of the identified genetic variants comprise the genetic variants having association with aneurysms with p-value of no more than about 10'2, about 10'3, about 10'4, about 10'5, about 10-6, about IO-7, about IO-8, about IO-9, about 1010, about 10u, about 1012, about 1013, about 10"14, about or 1015. In some embodiments, the identified genetic variants comprise the genetic variants having association with aneurysms with p-value of less than 5 x 10'8. In some embodiments, the identified genetic variants comprise genetic variants having association with aneurysms in high-risk subjects as compared to the rest of the reference population with odds ratio (OR) about 1.5 or greater, about 1.75 or greater, about 2.0 or greater, or about 2.25 or greater for the top 20% of the distribution; or about 1.5 or greater, about 1.75 or greater, about 2.0 or greater, about 2.25 or greater, about 2.5 or greater, or about 2.75 or greater. In some embodiments, the odds ratio (OR) may range from about 1.0 to about 1.5, from about 1.5 to about 2.0, from about 2.0 to about 2.5, from about 2.5 to about 3.0, from about 3.0 to about 3.5, from about 3.5 to about 4.0, from about 4.0 to about 4.5, from about 4.5 to about 5.0, from about 5.0 to about 5.5, from about 5.5 to about 6.0, from about 6.0 to about 6.5, from about 6.5 to about 7.0, or greater than 7.0. In some embodiments, high-risk subjects have aggregate burdens in the bottom decile, quintile, or tertile in a reference population. The threshold of the aggregate burden can be determined on the basis of the nature of the intended practical application and the risk difference that would be considered meaningful for that practical application.

[0186] In embodiments where the aggregate burden is determined for APOC3 genetic variants associated with aneurysms, then the aggregate burden represents a subject's risk score for developing an aneurysm. In some embodiments, the aggregate burden or risk score includes the APOC3 variant genomic nucleic acid molecule that comprises one or more of the genetic variations ll:116830491:A:T, ll:116830530:T:C, ll:116830568:A:G, ll:116830616:C:CT, 11:116830637:0:1, ll:116830638:G:A, ll:116830897:G:T, 11:116832769:G:A, ll:116832770:G:A, 11:116832882:T:G, ll:116830535:AC:A, ll:116830897:G:A, ll:116830898:T:A, 11:116832768:TG:T, 11:116832882:T:A, ll:116830491:A:C, ll:116830531:G:T, ll:116830542:GT:G, ll:116830584:T:C, ll:116830584:T:G, ll:116830638:G:T, ll:116830771:A:G, ll:116830868:C:T, ll:116830886:C:T, ll:116832805:G:A, 11:116832879:GCCTGAGA:G, ll:116830772:G:T, and 11:116832799:AC:A, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule. In some embodiments, a subject's aggregate burden can be determined for APOC3 genetic variants associated with an aneurysm in combination with additional genetic variants for other genes also associated with aneurysms to produce a polygenic risk score (PRS) for developing an aneurysm. In some embodiments, the PRS includes the APOC3 variant genomic nucleic acid molecule that comprises one or more of the genetic variations ll:116830491:A:T, ll:116830530:T:C, ll:116830568:A:G, ll:116830616:C:CT, ll:116830637:C:T, ll:116830638:G:A, ll:116830897:G:T, 11:116832769:G:A, ll:116832770:G:A, 11:116832882:T:G, ll:116830535:AC:A, ll:116830897:G:A, ll:116830898:T:A, 11:116832768:TG:T, 11:116832882:T:A, ll:116830491:A:C, ll:116830531:G:T, ll:116830542:GT:G, ll:116830584:T:C, ll:116830584:T:G, ll:116830638:G:T, ll:116830771:A:G, ll:116830868:C:T, ll:116830886:C:T, ll:116832805:G:A, 11:116832879:GCCTGAGA:G, ll:116830772:G:T, and 11:116832799:AC:A, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0187] The methods described herein can make use of a subject's aggregate burden of having LPA genetic variants associated with an increased risk of developing an aneurysm in combination with additional genetic variants for other genes also associated with aneurysm to produce a polygenic risk score (PRS) for developing an aneurysm. In some embodiments, the PRS includes the LPSD variant genomic nucleic acid molecules that comprise any one or more of the LPA genetic variations described herein. The PRS is the sum of two or more genetic variants that can be carried out in an association analysis with an increased risk of developing an aneurysm. When the subject has a higher PRS, the subject has an increased risk of developing an aneurysm, and the subject is a candidate for gene editing as described herein. When the subject has a lower PRS, the subject has a decreased risk of developing an aneurysm. The higher the PRS, the higher the risk of developing an aneurysm. In some embodiments, a subject's PRS represents a weighted sum of a plurality of any of the LPA variant nucleic acid molecules described herein. In some embodiments, the PRS is calculated using at least about 2, at least about 3, at least about 4, at least about 5, at least about 10, at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 100, at least about 120, at least about 150, at least about 200, at least about 250, at least about 300, at least about 400, or at least about 500 genetic variants present in or around (up to 10 Mb) the LPA gene, where the PRS is the number of alleles multiplied by the association estimate with an aneurysm or related outcome for each allele (e.g., a weighted polygenic burden score). In some embodiments, when the subject has a PRS higher than a desired threshold score, the subject has an increased risk of developing an aneurysm. In some embodiments, when the subject has a PRS lower than a desired threshold score, the subject has a decreased risk of developing an aneurysm.

[0188] In some embodiments, the LPA PRS may be divided into quintiles, e.g., top quintile, second quintile, intermediate quintile, fourth quintile, and bottom quintile, wherein the top quintile of PRS corresponds to the highest risk group and the bottom quintile of PRS corresponds to the lowest risk group. In some embodiments, a subject having a higher PRS comprises the highest weighted aggregate burdens, including, but not limited to PRS that is greater than the 60% percentile, greater than the 65% percentile, greater than the 70% percentile, greater than the 75% percentile, greater than the 80% percentile, greater than the 85% percentile, greater than the 90% percentile, or greater than the 95% percentile from a subject population (see, for example, Figure 9). In some embodiments, the genetic variants comprise the genetic variants having association with an aneurysm in the top 10%, top 20%, top 30%, top 40%, or top 50% of p-value range for the association. In some embodiments, each of the identified genetic variants comprise the genetic variants having association with an aneurysm with p-value of no more than about 10'2, about 10'3, about

[0189] IO-4, about 10-5, about 10-6, about IO-7, about IO-8, about IO-9, about 1010, about 1011, about 1012, about 1013, about 1014, about or 1015. In some embodiments, the identified genetic variants comprise the genetic variants having association with an aneurysm with p-value of less than 5 x 10'8. In some embodiments, the identified genetic variants comprise genetic variants having association with an aneurysm in high-risk subjects as compared to the rest of the reference population with odds ratio (OR) about 1.5 or greater, about 1.75 or greater, about 2.0 or greater, or about 2.25 or greater for the top 20% of the distribution; or about 1.5 or greater, about 1.75 or greater, about 2.0 or greater, about 2.25 or greater, about 2.5 or greater, or about 2.75 or greater. In some embodiments, the odds ratio (OR) may range from about 1.0 to about 1.5, from about 1.5 to about 2.0, from about 2.0 to about 2.5, from about 2.5 to about 3.0, from about 3.0 to about 3.5, from about 3.5 to about 4.0, from about 4.0 to about 4.5, from about 4.5 to about 5.0, from about 5.0 to about 5.5, from about 5.5 to about 6.0, from about 6.0 to about 6.5, from about 6.5 to about 7.0, or greater than 7.0. In some embodiments, low-risk subjects have PRS in the bottom decile, quintile, or tertile in a reference population. The threshold of the aggregate burden can be determined on the basis of the nature of the intended practical application and the risk difference that would be considered meaningful for that practical application.

[0190] The present disclosure also provides methods of detecting the presence or absence of an APOC3 variant nucleic acid molecule, a PCSK9 variant nucleic acid molecule, and / or an LPA variant nucleic acid molecule (i.e., a genomic nucleic acid molecule, an mRNA molecule, or a cDNA molecule produced from an mRNA molecule) in a biological sample from a subject. It is understood that gene sequences within a population and mRNA molecules encoded by such genes can vary due to polymorphisms such as single-nucleotide polymorphisms.

[0191] The biological sample can be derived from any cell, tissue, or biological fluid from the subject. The biological sample may comprise any clinically relevant tissue, such as a bone marrow sample, a tumor biopsy, a fine needle aspirate, or a sample of bodily fluid, such as blood, gingival crevicular fluid, plasma, serum, lymph, ascitic fluid, cystic fluid, or urine. In some cases, the sample comprises a buccal swab. The biological sample used in the methods disclosed herein can vary based on the assay format, nature of the detection method, and the tissues, cells, or extracts that are used as the sample. A biological sample can be processed differently depending on the assay being employed. For example, when detecting any APOC3 variant nucleic acid molecule, any PCSK9 variant nucleic acid molecule, and / or any LPA variant nucleic acid molecule, preliminary processing designed to isolate or enrich the biological sample for the genomic DNA can be employed. A variety of techniques may be used for this purpose. When detecting the level of any APOC3 variant nucleic acid molecule, any PCSK9 variant nucleic acid molecule, and / or any LPA variant nucleic acid molecule, different techniques can be used enrich the biological sample with mRNA molecules. Various methods to detect the presence or level of an mRNA molecule orthe presence of a particular variant genomic DNA locus can be used. In some embodiments, detecting an APOC3 variant nucleic acid molecule in a subject comprises performing a sequence analysis on a biological sample obtained from the subject to determine whether an APOC3 genomic nucleic acid molecule in the biological sample, and / or an APOC3 mRNA molecule in the biological sample, and / or an APOC3 cDNA molecule produced from an mRNA molecule in the biological sample, is present in the sample. In some embodiments, the methods detect the APOC3 variant genomic nucleic acid molecule that comprises one or more of the genetic variations ll:116830491:A:T, ll:116830530:T:C, ll:116830568:A:G, ll:116830616:C:CT, ll:116830637:C:T, ll:116830638:G:A, ll:116830897:G:T, 11:116832769:G:A, ll:116832770:G:A, 11:116832882:T:G, ll:116830535:AC:A, ll:116830897:G:A, ll:116830898:T:A, 11:116832768:TG:T, 11:116832882:T:A, ll:116830491:A:C, ll:116830531:G:T, ll:116830542:GT:G, ll:116830584:T:C, ll:116830584:T:G, ll:116830638:G:T, ll:116830771:A:G, ll:116830868:C:T, ll:116830886:C:T, ll:116832805:G:A, 11:116832879:GCCTGAGA:G, ll:116830772:G:T, and 11:116832799:AC:A, or an mRNA molecule produced therefrom, or a cDNA molecule produced from the mRNA molecule.

[0192] In some embodiments, the methods of detecting the presence or absence of an APOC3 variant nucleic acid molecule (such as, for example, a genomic nucleic acid molecule, an mRNA molecule, and / or a cDNA molecule produced from an mRNA molecule) in a subject comprise performing an assay on a biological sample obtained from the subject. The assay determines whether a nucleic acid molecule in the biological sample comprises a particular nucleotide sequence.

[0193] In some embodiments, the biological sample comprises a cell or cell lysate. Such methods can further comprise, for example, obtaining a biological sample from the subject comprising an APOC3 genomic nucleic acid molecule or mRNA molecule, and if mRNA, optionally reverse transcribing the mRNA into cDNA. Such assays can comprise, for example determining the identity of these positions of the particular APOC3 nucleic acid molecule. In some embodiments, the method is an in vitro method.

[0194] In some embodiments, the determining step, detecting step, or sequence analysis comprises sequencing at least a portion of the nucleotide sequence of the APOC3 genomic nucleic acid molecule, the APOC3 mRNA molecule, or the APOC3 cDNA molecule in the biological sample that comprises a genetic variation compared to the corresponding APOC3 reference molecule. In some embodiments, the sequenced portion comprises one or more variations that cause a loss-of-function (partial or complete) or are predicted to cause a loss-of- function (partial or complete).

[0195] In some embodiments, the assay comprises sequencing the entire nucleic acid molecule. In some embodiments, only an APOC3 genomic nucleic acid molecule is analyzed. In some embodiments, only an APOC3 mRNA is analyzed. In some embodiments, only an APOC3 cDNA obtained from the APOC3 mRNA is analyzed.

[0196] In some embodiments, detecting a PCSK9 variant nucleic acid molecule in a subject comprises performing a sequence analysis on a biological sample obtained from the subject to determine whether a PCSK9 genomic nucleic acid molecule in the biological sample, and / or a PCSK9 mRNA molecule in the biological sample, and / or a PCSK9 cDNA molecule produced from an mRNA molecule in the biological sample, is present in the sample. In some embodiments, the methods detect the PCSK9 variant genomic nucleic acid molecule that comprises one or more of the genetic variations disclosed herein, or an mRNA molecule produced therefrom, or a cDNA molecule produced from the mRNA molecule.

[0197] In some embodiments, the methods of detecting the presence or absence of a PCSK9 variant nucleic acid molecule (such as, for example, a genomic nucleic acid molecule, an mRNA molecule, and / or a cDNA molecule produced from an mRNA molecule) in a subject comprise performing an assay on a biological sample obtained from the subject. The assay determines whether a nucleic acid molecule in the biological sample comprises a particular nucleotide sequence.

[0198] In some embodiments, the biological sample comprises a cell or cell lysate. Such methods can further comprise, for example, obtaining a biological sample from the subject comprising a PCSK9 genomic nucleic acid molecule or mRNA molecule, and if mRNA, optionally reverse transcribing the mRNA into cDNA. Such assays can comprise, for example determining the identity of these positions of the particular PCSK9 nucleic acid molecule. In some embodiments, the method is an in vitro method.

[0199] In some embodiments, the determining step, detecting step, or sequence analysis comprises sequencing at least a portion of the nucleotide sequence of the PCSK9 genomic nucleic acid molecule, the PCSK9 mRNA molecule, or the PCSK9 cDNA molecule in the biological sample that comprises a genetic variation compared to the corresponding PCSK9 reference molecule. In some embodiments, the sequenced portion comprises one or more variations that cause a loss-of-function (partial or complete) or are predicted to cause a loss-of-function (partial or complete).

[0200] In some embodiments, the assay comprises sequencing the entire nucleic acid molecule. In some embodiments, only a PCSK9 genomic nucleic acid molecule is analyzed. In some embodiments, only a PCSK9 mRNA is analyzed. In some embodiments, only a PCSK9 cDNA obtained from the PCSK9 mRNA is analyzed.

[0201] In some embodiments, detecting an LPA variant nucleic acid molecule in a subject comprises performing a sequence analysis on a biological sample obtained from the subject to determine whether an LPA genomic nucleic acid molecule in the biological sample, and / or an LPA mRNA molecule in the biological sample, and / or an LPA cDNA molecule produced from an mRNA molecule in the biological sample, is present in the sample. In some embodiments, the methods detect the LPA variant genomic nucleic acid molecule that comprises one or more of the genetic variations disclosed herein, or an mRNA molecule produced therefrom, or a cDNA molecule produced from the mRNA molecule.

[0202] In some embodiments, the methods of detecting the presence or absence of an LPA variant nucleic acid molecule (such as, for example, a genomic nucleic acid molecule, an mRNA molecule, and / or a cDNA molecule produced from an mRNA molecule) in a subject comprise performing an assay on a biological sample obtained from the subject. The assay determines whether a nucleic acid molecule in the biological sample comprises a particular nucleotide sequence.

[0203] In some embodiments, the biological sample comprises a cell or cell lysate. Such methods can further comprise, for example, obtaining a biological sample from the subject comprising an LPA genomic nucleic acid molecule or mRNA molecule, and if mRNA, optionally reverse transcribing the mRNA into cDNA. Such assays can comprise, for example determining the identity of these positions of the particular LPA nucleic acid molecule. In some embodiments, the method is an in vitro method.

[0204] In some embodiments, the determining step, detecting step, or sequence analysis comprises sequencing at least a portion of the nucleotide sequence of the LPA genomic nucleic acid molecule, the LPA mRNA molecule, or the LPA cDNA molecule in the biological sample that comprises a genetic variation compared to the corresponding LPA reference molecule. In some embodiments, the sequenced portion comprises one or more variations that cause a loss-of- function (partial or complete) or are predicted to cause a gain-of-f unction (partial or complete) or an increase in expression.

[0205] In some embodiments, the assay comprises sequencing the entire nucleic acid molecule. In some embodiments, only an LPA genomic nucleic acid molecule is analyzed. In some embodiments, only an LPA mRNA is analyzed. In some embodiments, only an LPA cDNA obtained from the LPA mRNA is analyzed.

[0206] Alteration-specific polymerase chain reaction techniques can be used to detect mutations such as SNPs in a nucleic acid sequence. Alteration-specific primers can be used because the DNA polymerase will not extend when a mismatch with the template is present.

[0207] In some embodiments, the nucleic acid molecule in the sample is mRNA and the mRNA is reverse-transcribed into a cDNA prior to the amplifying step. In some embodiments, the nucleic acid molecule is present within a cell obtained from the subject.

[0208] In some embodiments, the assay comprises contacting the biological sample with a primer or probe, such as an alteration-specific primer or alteration-specific probe, that specifically hybridizes to an APOC3 variant genomic sequence, variant mRNA sequence, or variant cDNA sequence and not the corresponding APOC3 reference sequence under stringent conditions and determining whether hybridization has occurred.

[0209] In some embodiments, the determining step, detecting step, or sequence analysis comprises: a) amplifying at least a portion of the APOC3 nucleic acid molecule that encodes the APOC3 polypeptide; b) labeling the amplified nucleic acid molecule with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising an alteration-specific probe; and d) detecting the detectable label.

[0210] In some embodiments, the methods utilize probes and primers of sufficient nucleotide length to bind to the target nucleotide sequence and specifically detect and / or identify a polynucleotide comprising an APOC3 variant genomic nucleic acid molecule, variant mRNA molecule, or variant cDNA molecule. The hybridization conditions or reaction conditions can be determined by the operator to achieve this result. The nucleotide length may be any length that is sufficient for use in a detection method of choice, including any assay described or exemplified herein. Such probes and primers can hybridize specifically to a target nucleotide sequence under high stringency hybridization conditions. Probes and primers may have complete nucleotide sequence identity of contiguous nucleotides within the target nucleotide sequence, although probes differing from the target nucleotide sequence and that retain the ability to specifically detect and / or identify a target nucleotide sequence may be designed by conventional methods. Probes and primers can have about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% sequence identity or complementarity with the nucleotide sequence of the target nucleic acid molecule.

[0211] In some embodiments, the assay comprises contacting the biological sample with a primer or probe, such as an alteration-specific primer or alteration-specific probe, that specifically hybridizes to a PCSK9 variant genomic sequence, variant mRNA sequence, or variant cDNA sequence and not the corresponding PCSK9 reference sequence under stringent conditions and determining whether hybridization has occurred.

[0212] In some embodiments, the determining step, detecting step, or sequence analysis comprises: a) amplifying at least a portion of the PCSK9 nucleic acid molecule that encodes the PCSK9 polypeptide; b) labeling the amplified nucleic acid molecule with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising an alteration-specific probe; and d) detecting the detectable label.

[0213] In some embodiments, the methods utilize probes and primers of sufficient nucleotide length to bind to the target nucleotide sequence and specifically detect and / or identify a polynucleotide comprising a PCSK9 variant genomic nucleic acid molecule, variant mRNA molecule, or variant cDNA molecule. The hybridization conditions or reaction conditions can be determined by the operator to achieve this result. The nucleotide length may be any length that is sufficient for use in a detection method of choice, including any assay described or exemplified herein. Such probes and primers can hybridize specifically to a target nucleotide sequence under high stringency hybridization conditions. Probes and primers may have complete nucleotide sequence identity of contiguous nucleotides within the target nucleotide sequence, although probes differing from the target nucleotide sequence and that retain the ability to specifically detect and / or identify a target nucleotide sequence may be designed by conventional methods. Probes and primers can have about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% sequence identity or complementarity with the nucleotide sequence of the target nucleic acid molecule.

[0214] In some embodiments, the assay comprises contacting the biological sample with a primer or probe, such as an alteration-specific primer or alteration-specific probe, that specifically hybridizes to an LPA variant genomic sequence, variant mRNA sequence, or variant cDNA sequence and not the corresponding LPA reference sequence under stringent conditions and determining whether hybridization has occurred.

[0215] In some embodiments, the determining step, detecting step, or sequence analysis comprises: a) amplifying at least a portion of the LPA nucleic acid molecule that encodes the Lp(a); b) labeling the amplified nucleic acid molecule with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising an alteration-specific probe; and d) detecting the detectable label.

[0216] In some embodiments, the methods utilize probes and primers of sufficient nucleotide length to bind to the target nucleotide sequence and specifically detect and / or identify a polynucleotide comprising an LPA variant genomic nucleic acid molecule, variant mRNA molecule, or variant cDNA molecule. The hybridization conditions or reaction conditions can be determined by the operator to achieve this result. The nucleotide length may be any length that is sufficient for use in a detection method of choice, including any assay described or exemplified herein. Such probes and primers can hybridize specifically to a target nucleotide sequence under high stringency hybridization conditions. Probes and primers may have complete nucleotide sequence identity of contiguous nucleotides within the target nucleotide sequence, although probes differing from the target nucleotide sequence and that retain the ability to specifically detect and / or identify a target nucleotide sequence may be designed by conventional methods. Probes and primers can have about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% sequence identity or complementarity with the nucleotide sequence of the target nucleic acid molecule.

[0217] In some embodiments, the assay comprises RNA sequencing (RNA-Seq). In some embodiments, the assays also comprise reverse transcribing mRNA into cDNA, such as by the reverse transcriptase polymerase chain reaction (RT-PCR).

[0218] Illustrative examples of nucleic acid sequencing techniques include, but are not limited to, chain terminator (Sanger) sequencing and dye terminator sequencing. Other methods involve nucleic acid hybridization methods other than sequencing, including using labeled primers or probes directed against purified DNA, amplified DNA, and fixed cell preparations (fluorescence in situ hybridization (FISH)). In some methods, a target nucleic acid molecule may be amplified prior to or simultaneous with detection. Illustrative examples of nucleic acid amplification techniques include, but are not limited to, polymerase chain reaction (PCR), ligase chain reaction (LCR), strand displacement amplification (SDA), and nucleic acid sequence based amplification (NASBA). Other methods include, but are not limited to, ligase chain reaction, strand displacement amplification, and thermophilic SDA (tSDA).

[0219] In hybridization techniques, stringent conditions can be employed such that a probe or primer will specifically hybridize to its target. In some embodiments, a polynucleotide primer or probe under stringent conditions will hybridize to its target sequence to a detectably greater degree than to other non-target sequences, such as, at least 2-fold, at least 3-fold, at least 4- fold, or more over background, including over 10-fold over background. In some embodiments, a polynucleotide primer or probe under stringent conditions will hybridize to its target nucleotide sequence to a detectably greater degree than to other nucleotide sequences by at least 2-fold. In some embodiments, a polynucleotide primer or probe under stringent conditions will hybridize to its target nucleotide sequence to a detectably greater degree than to other nucleotide sequences by at least 3-fold. In some embodiments, a polynucleotide primer or probe under stringent conditions will hybridize to its target nucleotide sequence to a detectably greater degree than to other nucleotide sequences by at least 4-fold. In some embodiments, a polynucleotide primer or probe under stringent conditions will hybridize to its target nucleotide sequence to a detectably greater degree than to other nucleotide sequences by over 10-fold over background. Stringent conditions are sequence-dependent and will be different in different circumstances.

[0220] Appropriate stringency conditions which promote DNA hybridization, for example, 6X sodium chloride / sodium citrate (SSC) at about 45°C., followed by a wash of 2X SSC at 50°C, are known or can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6. Typically, stringent conditions for hybridization and detection will be those in which the salt concentration is less than about 1.5 M Na+ion, typically about 0.01 to 1.0 M Na+ion concentration (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30°C for short probes (such as, for example, 10 to 50 nucleotides) and at least about 60°C for longer probes (such as, for example, greater than 50 nucleotides). Stringent conditions may also be achieved with the addition of destabilizing agents such as formamide. Optionally, wash buffers may comprise about 0.1% to about 1% SDS. Duration of hybridization is generally less than about 24 hours, usually about 4 to about 12 hours. The duration of the wash time will be at least a length of time sufficient to reach equilibrium. In some embodiments, such isolated nucleic acid molecules comprise or consist of at least about 5, at least about 8, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 55, at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 85, at least about 90, at least about 95, at least about 100, at least about 200, at least about 300, at least about 400, at least about 500, at least about 600, at least about 700, at least about 800, at least about 900, at least about 1000, at least about 2000, at least about 3000, at least about 4000, or at least about 5000 nucleotides. In some embodiments, such isolated nucleic acid molecules comprise or consist of at least about 5, at least about 8, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, or at least about 25 nucleotides. In some embodiments, the isolated nucleic acid molecules comprise or consist of at least about 18 nucleotides. In some embodiments, the isolated nucleic acid molecules comprise or consists of at least about 15 nucleotides. In some embodiments, the isolated nucleic acid molecules consist of or comprise from about 10 to about 35, from about 10 to about 30, from about 10 to about 25, from about 12 to about 30, from about 12 to about 28, from about 12 to about 24, from about 15 to about 30, from about 15 to about 25, from about 18 to about 30, from about 18 to about 25, from about 18 to about 24, or from about 18 to about 22 nucleotides. In some embodiments, the isolated nucleic acid molecules consist of or comprise from about 18 to about 30 nucleotides. In some embodiments, the isolated nucleic acid molecules comprise or consist of at least about 15 nucleotides to at least about 35 nucleotides.

[0221] In some embodiments, such isolated nucleic acid molecules hybridize to APOC3 variant nucleic acid molecules (such as genomic nucleic acid molecules, mRNA molecules, and / or cDNA molecules) under stringent conditions. Such nucleic acid molecules can be used, for example, as probes, primers, alteration-specific probes, or alteration-specific primers as described or exemplified herein, and include, without limitation primers, probes, antisense RNAs, shRNAs, and siRNAs, each of which is described in more detail elsewhere herein and can be used in any of the methods described herein. In some embodiments, the isolated nucleic acid molecules hybridize to at least about 15 contiguous nucleotides of a nucleic acid molecule that is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to APOC3 variant nucleic acid molecules. In some embodiments, the isolated nucleic acid molecules consist of or comprise from about 15 to about 100 nucleotides, or from about 15 to about 35 nucleotides. In some embodiments, the isolated nucleic acid molecules consist of or comprise from about 15 to about 100 nucleotides. In some embodiments, the isolated nucleic acid molecules consist of or comprise from about 15 to about 35 nucleotides.

[0222] In some embodiments, such isolated nucleic acid molecules hybridize to PCSK9 variant nucleic acid molecules (such as genomic nucleic acid molecules, mRNA molecules, and / or cDNA molecules) under stringent conditions. Such nucleic acid molecules can be used, for example, as probes, primers, alteration-specific probes, or alteration-specific primers as described or exemplified herein.

[0223] In some embodiments, the isolated nucleic acid molecules hybridize to at least about 15 contiguous nucleotides of a nucleic acid molecule that is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to PCSK9 variant nucleic acid molecules. In some embodiments, the isolated nucleic acid molecules consist of or comprise from about 15 to about 100 nucleotides, or from about 15 to about 35 nucleotides. In some embodiments, the isolated nucleic acid molecules consist of or comprise from about 15 to about 100 nucleotides. In some embodiments, the isolated nucleic acid molecules consist of or comprise from about 15 to about 35 nucleotides.

[0224] In some embodiments, such isolated nucleic acid molecules hybridize to LPA variant nucleic acid molecules (such as genomic nucleic acid molecules, mRNA molecules, and / or cDNA molecules) under stringent conditions. Such nucleic acid molecules can be used, for example, as probes, primers, alteration-specific probes, or alteration-specific primers as described or exemplified herein.

[0225] In some embodiments, the isolated nucleic acid molecules hybridize to at least about 15 contiguous nucleotides of a nucleic acid molecule that is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to LPA variant nucleic acid molecules. In some embodiments, the isolated nucleic acid molecules consist of or comprise from about 15 to about 100 nucleotides, or from about 15 to about 35 nucleotides. In some embodiments, the isolated nucleic acid molecules consist of or comprise from about 15 to about 100 nucleotides. In some embodiments, the isolated nucleic acid molecules consist of or comprise from about 15 to about 35 nucleotides.

[0226] In some embodiments, the alteration-specific probes and alteration-specific primers comprise DNA. In some embodiments, the alteration-specific probes and alteration-specific primers comprise RNA.

[0227] In some embodiments, the probes and primers described herein (including alterationspecific probes and alteration-specific primers) have a nucleotide sequence that specifically hybridizes to any of the nucleic acid molecules disclosed herein, or the complement thereof. In some embodiments, the probes and primers specifically hybridize to any of the nucleic acid molecules disclosed herein under stringent conditions.

[0228] In some embodiments, the primers, including alteration-specific primers, can be used in second generation sequencing or high throughput sequencing. In some instances, the primers, including alteration-specific primers, can be modified. In particular, the primers can comprise various modifications that are used at different steps of, for example, Massive Parallel Signature Sequencing (MPSS), Polony sequencing, and 454 Pyrosequencing. Modified primers can be used at several steps of the process, including biotinylated primers in the cloning step and fluorescently labeled primers used at the bead loading step and detection step. Polony sequencing is generally performed using a paired-end tags library wherein each molecule of DNA template is about 135 bp in length. Biotinylated primers are used at the bead loading step and emulsion PCR. Fluorescently labeled degenerate nonamer oligonucleotides are used at the detection step. An adaptor can contain a 5'-biotin tag for immobilization of the DNA library onto streptavidin-coated beads.

[0229] The probes and primers described herein can be used to detect a nucleotide variation within any of the APOC3 variant nucleic acid molecules disclosed herein. The primers described herein can be used to amplify any APOC3 variant nucleic acid molecule, or a fragment thereof.

[0230] In the context of the disclosure "specifically hybridizes" means that the probe or primer (such as, for example, the alteration-specific probe or alteration-specific primer) does not hybridize to a nucleic acid sequence encoding an APOC3 reference genomic nucleic acid molecule, an APOC3 reference mRNA molecule, and / or an APOC3 reference cDNA molecule. The probes and primers described herein can be used to detect a nucleotide variation within any of the PCSK9 variant nucleic acid molecules disclosed herein. The primers described herein can be used to amplify any PCSK9 variant nucleic acid molecule, or a fragment thereof.

[0231] In the context of the disclosure "specifically hybridizes" means that the probe or primer (such as, for example, the alteration-specific probe or alteration-specific primer) does not hybridize to a nucleic acid sequence encoding a PCSK9 reference genomic nucleic acid molecule, a PCSK9 reference mRNA molecule, and / or a PCSK9 reference cDNA molecule.

[0232] The probes and primers described herein can be used to detect a nucleotide variation within any of the LPA variant nucleic acid molecules disclosed herein. The primers described herein can be used to amplify any LPA variant nucleic acid molecule, or a fragment thereof.

[0233] In the context of the disclosure "specifically hybridizes" means that the probe or primer (such as, for example, the alteration-specific probe or alteration-specific primer) does not hybridize to a nucleic acid sequence encoding an LPA reference genomic nucleic acid molecule, an LPA reference mRNA molecule, and / or an LPA reference cDNA molecule.

[0234] In some embodiments, the probes (such as, for example, an alteration-specific probe) comprise a label. In some embodiments, the label is a fluorescent label, a radiolabel, or biotin.

[0235] The present disclosure also provides supports comprising a substrate to which any one or more of the probes disclosed herein is attached. Solid supports are solid-state substrates or supports with which molecules, such as any of the probes disclosed herein, can be associated. A form of solid support is an array. Another form of solid support is an array detector. An array detector is a solid support to which multiple different probes have been coupled in an array, grid, or other organized pattern. A form for a solid-state substrate is a microtiter dish, such as a standard 96-well type. In some embodiments, a multiwell glass slide can be employed that normally contains one array per well.

[0236] The genomic nucleic acid molecules, mRNA molecules, and cDNA molecules can be from any organism. For example, the genomic nucleic acid molecules, mRNA molecules, and cDNA molecules can be human or an ortholog from another organism, such as a non-human mammal, a rodent, a mouse, or a rat. It is understood that gene sequences within a population can vary due to polymorphisms such as single-nucleotide polymorphisms.

[0237] Also provided herein are functional polynucleotides that can interact with the disclosed nucleic acid molecules. Examples of functional polynucleotides include, but are not limited to, antisense molecules, aptamers, ribozymes, triplex forming molecules, and external guide sequences. The functional polynucleotides can act as effectors, inhibitors, modulators, and stimulators of a specific activity possessed by a target molecule, or the functional polynucleotides can possess a de novo activity independent of any other molecules.

[0238] The isolated nucleic acid molecules disclosed herein can comprise RNA, DNA, or both RNA and DNA. The isolated nucleic acid molecules can also be linked or fused to a heterologous nucleic acid sequence, such as in a vector, or a heterologous label. For example, the isolated nucleic acid molecules disclosed herein can be within a vector or as an exogenous donor sequence comprising the isolated nucleic acid molecule and a heterologous nucleic acid sequence. The isolated nucleic acid molecules can also be linked or fused to a heterologous label. The label can be directly detectable (such as, for example, fluorophore) or indirectly detectable (such as, for example, hapten, enzyme, or fluorophore quencher). Such labels can be detectable by spectroscopic, photochemical, biochemical, immunochemical, or chemical means. Such labels include, for example, radiolabels, pigments, dyes, chromogens, spin labels, and fluorescent labels. The label can also be, for example, a chemiluminescent substance; a metal-containing substance; or an enzyme, where there occurs an enzyme-dependent secondary generation of signal. The term "label" can also refer to a "tag" or hapten that can bind selectively to a conjugated molecule such that the conjugated molecule, when added subsequently along with a substrate, is used to generate a detectable signal. For example, biotin can be used as a tag along with an avidin or streptavidin conjugate of horseradish peroxidate (HRP) to bind to the tag, and examined using a calorimetric substrate (such as, for example, tetramethylbenzidine (TMB)) or a fluorogenic substrate to detect the presence of HRP. Exemplary labels that can be used as tags to facilitate purification include, but are not limited to, myc, HA, FLAG or 3XFLAG, 6Xhis or polyhistidine, glutathione-S-transferase (GST), maltose binding protein, an epitope tag, or the Fc portion of immunoglobulin. Numerous labels include, for example, particles, fluorophores, haptens, enzymes and their calorimetric, fluorogenic and chemiluminescent substrates and other labels.

[0239] Percent identity (or percent complementarity) between particular stretches of nucleotide sequences within nucleic acid molecules or amino acid sequences within polypeptides can be determined routinely using BLAST programs (basic local alignment search tools) and PowerBLAST programs (Altschul et al., J. Mol. Biol., 1990, 215, 403-410; Zhang and Madden, Genome Res., 1997, 7, 649-656) or by using the Gap program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, Madison Wis.), using default settings, which uses the algorithm of Smith and Waterman (Adv. Appl. Math., 1981, 2, 482-489). Herein, if reference is made to percent sequence identity, the higher percentages of sequence identity are preferred over the lower ones.

[0240] The present disclosure also provides aneurysm therapeutic agents for use in treating an aneurysm, preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm in a subject having an APOC3 variant nucleic acid molecule. Any of the aneurysm therapeutic agents described herein can be used herein. Any of the APOC3 variant nucleic acid molecules disclosed herein can be used herein. In some embodiments, the APOC3 variant nucleic acid molecule is a APOC3 variant genomic nucleic acid molecule that comprises one or more of the genetic variations ll:116830491:A:T, ll:116830530:T:C, ll:116830568:A:G, ll:116830616:C:CT, ll:116830637:C:T, ll:116830638:G:A, ll:116830897:G:T, 11:116832769:G:A, ll:116832770:G:A, 11:116832882:T:G, ll:116830535:AC:A, ll:116830897:G:A, ll:116830898:T:A, 11:116832768:TG:T, 11:116832882:T:A, ll:116830491:A:C, ll:116830531:G:T, ll:116830542:GT:G, ll:116830584:T:C, ll:116830584:T:G, ll:116830638:G:T, ll:116830771:A:G, ll:116830868:C:T, ll:116830886:C:T, ll:116832805:G:A, 11:116832879:GCCTGAGA:G, ll:116830772:G:T, and 11:116832799:AC:A, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0241] The present disclosure also provides aneurysm therapeutic agents for use in the preparation of a medicament for use in treating an aneurysm, preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm in a subject having an APOC3 variant nucleic acid molecule. Any of the aneurysm therapeutic agents described herein can be used herein. Any of the APOC3 variant nucleic acid molecules disclosed herein can be used herein. In some embodiments, the APOC3 variant nucleic acid molecule is an APOC3 variant genomic nucleic acid molecule that comprises one or more of the genetic variations ll:116830491:A:T, ll:116830530:T:C, ll:116830568:A:G, ll:116830616:C:CT, ll:116830637:C:T, ll:116830638:G:A, ll:116830897:G:T, 11:116832769:G:A, ll:116832770:G:A, 11:116832882:T:G, ll:116830535:AC:A, ll:116830897:G:A, ll:116830898:T:A, 11:116832768:TG:T, 11:116832882:T:A, ll:116830491:A:C, ll:116830531:G:T, ll:116830542:GT:G, ll:116830584:T:C, ll:116830584:T:G, ll:116830638:G:T, ll:116830771:A:G, ll:116830868:C:T, ll:116830886:C:T, ll:116832805:G:A, 11:116832879:GCCTGAGA:G, ll:116830772:G:T, and 11:116832799:AC:A, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0242] The present disclosure also provides APOC3 inhibitors for use in treating an aneurysm, preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm in a subject that is APOC3 reference or is heterozygous for an APOC3 variant nucleic acid molecule. Any of the APOC3 inhibitors described herein can be used herein. Any of the APOC3 variant nucleic acid molecules disclosed herein can be used herein. In some embodiments, the APOC3 variant nucleic acid molecule is an APOC3 variant genomic nucleic acid molecule that comprises one or more of the genetic variations ll:116830491:A:T, ll:116830530:T:C, ll:116830568:A:G, ll:116830616:C:CT, ll:116830637:C:T, ll:116830638:G:A, ll:116830897:G:T, 11:116832769:G:A, ll:116832770:G:A, 11:116832882:T:G, ll:116830535:AC:A, ll:116830897:G:A, ll:116830898:T:A, 11:116832768:TG:T, 11:116832882:T:A, ll:116830491:A:C, ll:116830531:G:T, ll:116830542:GT:G, ll:116830584:T:C, ll:116830584:T:G, ll:116830638:G:T, ll:116830771:A:G, ll:116830868:C:T, ll:116830886:C:T, ll:116832805:G:A, 11:116832879:GCCTGAGA:G, ll:116830772:G:T, and 11:116832799:AC:A, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0243] The present disclosure also provides APOC3 inhibitors for use in the preparation of a medicament for treating an aneurysm, preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm in a subject that is APOC3 reference or is heterozygous for an APOC3 variant nucleic acid molecule. Any of the APOC3 inhibitors described herein can be used herein. Any of the APOC3 variant nucleic acid molecules disclosed herein can be used herein. In some embodiments, the APOC3 variant nucleic acid molecule is an APOC3 variant genomic nucleic acid molecule that comprises one or more of the genetic variations ll:116830491:A:T, ll:116830530:T:C, ll:116830568:A:G, ll:116830616:C:CT, ll:116830637:C:T, ll:116830638:G:A, ll:116830897:G:T, 11:116832769:G:A, ll:116832770:G:A, 11:116832882:T:G, ll:116830535:AC:A, ll:116830897:G:A, ll:116830898:T:A, 11:116832768:TG:T, 11:116832882:T:A, ll:116830491:A:C, ll:116830531:G:T, ll:116830542:GT:G, ll:116830584:T:C, ll:116830584:T:G, ll:116830638:G:T, ll:116830771:A:G, ll:116830868:C:T, ll:116830886:C:T, ll:116832805:G:A, 11:116832879:GCCTGAGA:G, ll:116830772:G:T, and 11:116832799:AC:A, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0244] In any of the embodiments described herein, wherein more than one compound (e.g., APOC3 inhibitor, PSCK9 inhibitor, LPA inhibitor, CETP inhibitor, aneurysm therapeutic agent, etc.) is administered to a subject, each compound can be administered independent of any other compound (e.g., separate pharmaceutical compositions; i.e., a first pharmaceutical composition comprising a first compound and a second pharmaceutical composition comprising a second compound; etc. for a third pharmaceutical composition comprising a third compound). In some embodiments, the first pharmaceutical composition and the subsequent pharmaceutical composition (i.e., second and / or third) are administered simultaneously. In some embodiments, the first pharmaceutical composition is administered before the subsequent pharmaceutical composition (i.e., second and / orthird). In some embodiments, the first pharmaceutical composition is administered after the subsequent pharmaceutical composition (i.e., second and / or third).

[0245] In any of the embodiments described herein, wherein more than one compound (e.g., APOC3 inhibitor, PSCK9 inhibitor, LPA inhibitor, CETP inhibitor, aneurysm therapeutic agent, etc.) is administered to a subject, the one or more compounds can be combined into a single pharmaceutical composition (e.g., a pharmaceutical composition, such as an i.v. bag, containing two or three compounds).

[0246] In any of the embodiments described herein, wherein more than one compound (e.g., APOC3 inhibitor, PSCK9 inhibitor, LPA inhibitor, CETP inhibitor, aneurysm therapeutic agent, etc.) is administered to a subject, the one or more compounds can be linked together to form a single compound for administration. Thus, for example, the APOC inhibitor can be linked to the CETP inhibitor, or PCSK9 inhibitor of different ratios through a cleavable or degradable linker to form a unimolecular compound, and likewise for all of the compounds described herein.

[0247] All patent documents, websites, other publications, accession numbers and the like cited above or below are incorporated by reference in their entirety for all purposes to the same extent as if each individual item were specifically and individually indicated to be so incorporated by reference. If different versions of a sequence are associated with an accession number at different times, the version associated with the accession number at the effective filing date of this application is meant. The effective filing date means the earlier of the actual filing date or filing date of a priority application referring to the accession number if applicable. Likewise, if different versions of a publication, website or the like are published at different times, the version most recently published at the effective filing date of the application is meant unless otherwise indicated. Any feature, step, element, embodiment, or aspect of the present disclosure can be used in combination with any other feature, step, element, embodiment, or aspect unless specifically indicated otherwise. Although the present disclosure has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims.

[0248] The following examples are provided to describe the embodiments in greater detail. They are intended to illustrate, not to limit, the claimed embodiments. The following examples provide those of ordinary skill in the art with a disclosure and description of how the compounds, compositions, articles, devices and / or methods described herein are made and evaluated and are intended to be purely exemplary and are not intended to limit the scope of any claims. Efforts have been made to ensure accuracy with respect to numbers (such as, for example, amounts, temperature, etc.), but some errors and deviations may be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

[0249] Examples

[0250] Example 1: Loss of Function of the Gene Encoding Apolipoprotein C3 (APOC3) is Associated with Lower Odds of Abdominal Aortic Aneurysm

[0251] The hypothesis of whether or not rare loss-of-function variations in APOC3 are associated with abdominal aortic aneurysms (AAA) was examined. Exome sequencing data for up to 679,274 participants from the Geisinger Heath System MyCode Community Health Initiative study (GHS), Malmo Diet and Cancer Study (MDCS), Mount Sinai's BioMe personalized medicine cohort (SINAI), the UK Biobank (UKB), the University of Pennsylvania Penn Medicine Biobank (UPENN-PMBB) and the Indiana Biobank (INDIANA) was analyzed. Compared to noncarriers, carriers of rare predicted loss-of-function variants in APOC3 lower levels of triglycerides and LDL cholesterol and higher levels of HDL cholesterol (see, Table 2). Carriers of rare predicted loss-of-function variants in APOC3 were at a lower risk of developing abdominal aortic aneurysms compared to non-carriers (see, Table 3). A total of 28 predicted loss of function variants contributed to the associations (see, Table 1). Table 2: Rare predicted loss of function variants in AP0C3 are associated with lower levels of triglycerides, LDL cholesterol and higher levels of HDL cholesterol

[0252] Effect sizes are given in standard deviation (SD) units. RR: count of homozygous individuals for the reference allele, RA: count of heterozygous individuals carrying one pLOF variant, AA: count of homozygous individuals carrying pLOF variants in both APOC3 alleles.

[0253] Table 3: Rare predicted loss of function variants in APOC3 are associated with lower odds of abdominal aortic aneurysm (AAA) Effect sizes are given in standard deviation (SD) units. RR: count of homozygous individuals for the reference allele, RA: count of heterozygous individuals carrying one pLOF variant, AA: count of homozygous individuals carrying pLOF variants in both APOC3 alleles.

[0254] Participating cohorts

[0255] Genetic association studies were performed in individuals of African or Admixed African, Admixed American, European, and East and South Asian ancestry from the United Kingdom Biobank (UKB) cohort (Bycroft et al., Nature, 2018, 562, 203-209; and Van Hout et al., Nature, 2020, 586, 749-756), the MyCode Community Health Initiative cohort from the Geisinger Health System (GHS) (Carey et al., Genet Med., 2016, 18, 906-13), the University of Pennsylvania Medicine BioBank (PMBB), the Malmo Diet and Cancer Study (MDCS) (Berglund et al., J. Intern. Med., 1993, 233, 45-51) , Mount Sinai's BioMe Personalized Medicine Cohort (SINAI) (Gottesnnan et al., Genet. Med., 2013, 15, 761-771) and the Indiana Biobank (INDIANA) is a health system-based cohort based in Indiana. The UKB is a population-based cohort study of people aged between 40 and 69 years recruited through 22 testing centers in the UK between 2006-2010. Exome sequencing and phenotype data were available for 446,475 individuals. The GHS MyCode study is a health system-based cohort of patients from Central and Eastern Pennsylvania (USA) recruited in 2007-2019. A total of 135,768 participants from GHS with available whole-exome sequencing and phenotype data were included. Mount Sinai's BioMe Personalized Medicine Cohort (SINAI) is an electronic health record-linked clinical care cohort, of which 26,501 individuals had available phenotypes and exome sequencing data and were included in analysis. The Malmo Diet and Cancer Study (MDCS) included 27,944 individuals with available phenotype and exome sequencing data. The University of Pennsylvania Medicine BioBank (PMBB) included a total of 37,197 individuals with available phenotype and exome sequencing data. The Indiana Biobank (INDIANA) included 5,389 participants with exome sequencing data.

[0256] Phenotype definitions

[0257] Lipid levels were measured during a visit to the assessment center for UK Biobank participants or were extracted from electronic health record datasets for participants from other contributing cohorts. Direct LDL measurements were available for UK biobank participants. LDL levels were calculated using the Friedewald equation for the other participating individuals. Individuals known to be on lipid lowering medication had their pretreatment LDL estimated using a correction factor for individuals known to be on lipid lowering medication.

[0258] Abdominal aortic aneurysms were defined as individuals with ICD10 codes: 1713, 1714, 1715 or 1716 or those with ICD9 codes: 4413, 4414, 4416 or 4417. Cases also included operation procedure codes from OPCS4 in UKB: L183, L184, L185, L186, L193, L194, L195, L196, L271, L272, L275, L276, L281, L282, L285 or L286. Cases also included operation procedure codes from NOMESCO in MDCS: PCG10, PDG10, PDG99, 3146, 8807, 8808, 0961 or 0962. Participants were excluded from controls if they had ICD10 codes Q254, S250, S350, 172, 1671, 1254 or A5201or if they had ICD9 codes 7472, 9010, 9020, 442, 4373, 0930. Those with OPSC4 codes K33, L16, L20, L21, L22, L23, L258, L268, K473, L33, L424, L464, L48, L49, L533, L56, L57, L623, L624, L705, O01, 002, 003, 004 were excluded from controls. Those with NOMESCO codes FCA, FCB, FCC, FCD, FCE, FCW, FDW, PAG, PCG, PCQ, PCR, PCU, PCW, PDG, PDN, PDP, PDQ, PDR, PDS, PDW, AAC00, AAC05, AAC1O, AAC15, AAC99, AALOO, PBG, PEG, PFG, 3144, 3139, 3142, 8812, 0190, 0191. Additional control exclusions for those self-reported cerebral aneurysms or leg aneurysms.

[0259] Association with protection from abdominal aortic aneurysm driven by the HDL-C raising effects of APOC3 mutations was examined. Results from analysis of human genetics data in about 8,000 cases and about 650,000 controls of abdominal aortic aneurysm shows a protective impact for HDL-C raising common variants (see, Figure 1, Panel A) and for pLOF variants in APOC3 which are associated with higher HDL-C (see, Figure 1, Panel A).

[0260] Common putative gain-of-function variant in CETP associated with higher abdominal aortic aneurysm risk was examined. Results from analysis of a gain-of-function variant (Ala390Pro) CETP variant reveals an association with a higher risk of abdominal aortic aneurysm (see, Figure 2, Panel A and Panel B).

[0261] Example 2: Effects of Selected CETP Inhibitors on Lipids

[0262] To demonstrate the ability of CETP inhibition to impact on the desired lipid particles that human genetics implicates in abdominal aortic aneurysm, data was extracted from publications on human randomized controlled trials of CETP inhibitors (i.e., obicetrapib and anacetrapib; see, Figure 3). Both CETP inhibitors resulted in reduced LDL cholesterol levels and increased HDL cholesterol levels compared to placebo (see, Figure 3).

[0263] Example 3: LDL-C and HDL-C Associated Variants Influence Abdominal Aortic Aneurysm Risk

[0264] Referring to Figure 4, higher H DL-C and lower LDL-C polygenic scores (PRS) associated with protection from AAA. HDL-C PRS does not influence risk of other cardiovascular diseases. PCSK9 loss-of-function variants lowered LDL-C and protected against coronary disease and AAA with similar effect size. APOC3 loss-of-function variants lowered LDL-C and raised HDL-C and protected against coronary disease and AAA, with a larger impact on AAA risk. The larger impact of APOC3 loss-of-function on AAA compared to coronary disease could be explained by its large HDL-C increasing effect on top of the LDL-C lowering effect.

[0265] Example 4: HDL-C is an Important Etiological Factor for Abdominal Aortic Aneurysm and LDL-C is a Causal Risk Factor for Abdominal Aortic Aneurysm and Coronary Artery Disease Referring to Figure 5, higher HDL-C polygenic score associated with protection from AAA. Higher HDL-C PRS showed minimal association with myocardial infarction (Ml). An HDL-C PRS that excludes LDL-C associated variants (p>0.5) is not associated with Ml but remains associated with AAA. Lower LDL-C PRS associated with protection from both AAA and Ml with similar effect size.

[0266] Example 5: APOC3 Rare Coding Variants Raise HDL-C and Protect from Abdominal Aortic Aneurysm

[0267] Referring to Figure 6, APOC3 rare coding variants raised HDL-C and protected from AAA.

[0268] Example 6: PCSK9 Rare Coding Variants Associate with Lower Risk of Abdominal Aortic Aneurysm

[0269] Referring to Figure 7 , PCSK9 rare coding variants associated with a lower risk of AAA.

[0270] Example 7: Analysis of ODYSSEY OUTCOMES Trial showing 41% Reduction in Abdominal Aortic Aneurysm Events with Alirocumab

[0271] Referring to Figure 8, new AAA occurred in 0.44% (41 / 9359) in the placebo group and 0.23% (22 / 9389) in the alirocumab group (HR (95% Cl): 0.55 (0.33, 0.92). At 12 months, AAA patients showed: i) a decrease in median LDL-C change from baseline of 54.4 mg / dl (53% reduction) in the alirocumab group vs. 0 mg / dl (0%) from baseline in the placebo group; and ii) an increase in median HDL-C change from baseline of 3.5 mg / dl (12.5% increase) in the alirocumab group vs. 0.7 mg / dl increase (1.9% increase) from baseline in the placebo group.

[0272] Example 8: Higher Lp(a) levels or LPA Genetic Score Associate with Higher Abdominal Aortic Aneurysm Risk

[0273] Referring to Figure 9, higher Lp(a) levels or LPA genetic score associated with higher AAA risk.

[0274] Example 9: Carriers of Both Low LPA Genetic Score and PCSK9 Protective 46L Allele were at

[0275] Lower Risk of AAA A genetic score predicted lipoprotein (a) levels was associated with AAA. Analysis of top tertile of LPA genetic score and PCSK9 R46L variant indicated an additive effect on AAA supportive of a combination therapy of lipoprotein (a) and PCSK9 inhibitors for treatment of AAA. Individuals who were carriers of both a low LPA genetic score and PCSK9 protective 46L allele were at lower risk of AAA with an odds ratio of 0.61, which was more pronounced than individuals with high LPA genetic risk and carriers of PCSK946L protective allele (odds ratio=0.77) and individuals with low LPA genetic risk and non-carriers of the PCSK946L protective allele (odds ratio=0.8) (see, Figure 10). Various modifications of the described subject matter, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference (including, but not limited to, journal articles, U.S. and non-U. S. patents, patent application publications, international patent application publications, gene bank accession numbers, and the like) cited in the present application is incorporated herein by reference in its entirety and for all purposes.

Claims

What is Claimed is:

1. A method of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, the method comprising administering an Apolipoprotein C3 (APOC3) inhibitor to the subject.

2. The method of claim 1, wherein the aneurysm is an abdominal aortic aneurysm, a thoracic aortic aneurysm, a cerebral aneurysm, a carotid aneurysm, a popliteal aneurysm, a mesenteric aneurysm, or a splenic aneurysm.

3. The method of claim 1, wherein the aneurysm is an abdominal aortic aneurysm.

4. The method of any one of claims 1 to 3, wherein the APOC3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an APOC3 nucleic acid molecule.

5. The method of claim 4, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), and / or a short hairpin RNA (shRNA).

6. The method of claim 5, wherein the inhibitory nucleic acid molecule comprises an siRNA.

7. The method of claim 5, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule.

8. The method of any one of claims 1 to 7, wherein the subject is also administered an aneurysm therapeutic agent or an aneurysm therapy.

9. The method of any one of claims 1 to 8, further comprising detecting the presence or absence of an APOC3 variant nucleic acid molecule in a biological sample from the subject.

10. The method of claim 9, further comprising administering an aneurysm therapeutic agent in an amount that is the same as or less than a standard dosage amount to the subject when the APOC3 variant nucleic acid molecule is absent from the biological sample.

11. The method of claim 9, further comprising administering an aneurysm therapeutic agent in an amount that is the same as or less than a standard dosage amount to the subject when the subject is heterozygous for the APOC3 variant nucleic acid molecule.

12. The method of any one of claims 9 to 11, wherein the APOC3 variant nucleic acid molecule comprises a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, a missense variant, an in-frame indel variant, and / or a variant that encodes a truncated APOC3 variant polypeptide.

13. The method of any one of claims 9 to 12, wherein the APOC3 variant nucleic acid molecule comprises one or more of the genetic variations ll:116830491:A:T, ll:116830530:T:C, ll:116830568:A:G, ll:116830616:C:CT, ll:116830637:C:T, ll:116830638:G:A, ll:116830897:G:T, 11:116832769:G:A, ll:116832770:G:A, 11:116832882:T:G, ll:116830535:AC:A, ll:116830897:G:A, ll:116830898:T:A, 11:116832768:TG:T, 11:116832882:T:A, ll:116830491:A:C, ll:116830531:G:T, ll:116830542:GT:G, ll:116830584:T:C, ll:116830584:T:G, ll:116830638:G:T, ll:116830771:A:G, ll:116830868:C:T, 11:116830886:0:7, ll:116832805:G:A, 11:116832879:GCCTGAGA:G, ll:116830772:G:T, and 11:116832799:AC:A.

14. A method of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, by administering an aneurysm therapeutic agent or an aneurysm therapy, the method comprising: determining or having determined whether the subject has an Apolipoprotein C3 (APOC3) variant nucleic acid molecule, by: obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising an APOC3 variant nucleic acid molecule; and administering or continuing to administer the aneurysm therapeutic agent in an amount that is the same as or less than a standard dosage amount or an aneurysm therapy, and / or an APOC3 inhibitor to a subject that is APOC3 reference; administering or continuing to administer the aneurysm therapeutic agent in an amount that is the same as or less than a standard dosage amount or an aneurysm therapy, and / or an APOC3 inhibitor to a subject that is heterozygous for the APOC3 variant nucleic acid molecule; or administering or continuing to administer the aneurysm therapeutic agent in a standard dosage amount or an aneurysm therapy to a subject that is homozygous for the APOC3 variant nucleic acid molecule; wherein the presence of the APOC3 variant nucleic acid molecule indicates the subject has a decreased risk of developing an aneurysm.

15. The method of claim 14, wherein the APOC3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an APOC3 nucleic acid molecule.

16. The method of claim 15, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), and / or a short hairpin RNA (shRNA).

17. The method of claim 15, wherein the inhibitory nucleic acid molecule comprises an siRNA.

18. The method of claim 15, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule.

19. The method of any one of claims 14 to 18, wherein the subject is heterozygous for the APOC3 variant nucleic acid molecule, and the subject is administered or continued to be administered an aneurysm therapeutic agent in an amount that is the same as or less than a standard dosage amount or an aneurysm therapy, and the APOC3 inhibitor.

20. The method of any one of claims 14 to 18, wherein the subject is APOC3 reference, and the subject is administered or continued to be administered an aneurysm therapeutic agent in an amount that is the same as or less than a standard dosage amount or an aneurysm therapy, and the APOC3 inhibitor.

21. The method of any one of claims 14 to 20, wherein the APOC3 variant nucleic acid molecule comprises a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, a missense variant, an in-frame indel variant, and / or a variant that encodes a truncated APOC3 variant polypeptide.

22. The method of any one of claims 14 to 21, wherein the APOC3 variant nucleic acid molecule comprises one or more of the genetic variations ll:116830491:A:T, ll:116830530:T:C, ll:116830568:A:G, ll:116830616:C:CT, ll:116830637:C:T, ll:116830638:G:A, ll:116830897:G:T, 11:116832769:G:A, ll:116832770:G:A, 11:116832882:T:G, ll:116830535:AC:A, ll:116830897:G:A, ll:116830898:T:A, 11:116832768:TG:T, 11:116832882:T:A, ll:116830491:A:C, ll:116830531:G:T, ll:116830542:GT:G, ll:116830584:T:C, ll:116830584:T:G, ll:116830638:G:T, ll:116830771:A:G, ll:116830868:C:T, ll:116830886:C:T, ll:116832805:G:A, 11:116832879:GCCTGAGA:G, ll:116830772:G:T, and 11:116832799:AC:A.

23. A method of identifying a subject having an increased risk of developing an aneurysm, the method comprising: determining or having determined the presence or absence of an Apolipoprotein C3 (APOC3) variant nucleic acid molecule in a biological sample obtained from the subject; wherein: when the subject is APOC3 reference, then the subject has an increased risk of developing an aneurysm; and when the subject is heterozygous or homozygous for the APOC3 variant nucleic acid molecule, then the subject has a decreased risk of developing an aneurysm.

24. The method of claim 23, wherein the APOC3 variant nucleic acid molecule is a splicesite variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, a missense variant, an in-frame indel variant, or a variant that encodes a truncated APOC3 variant polypeptide.

25. The method of claim 32 or claim 33, wherein the APOC3 variant nucleic acid molecule comprises one or more of the genetic variations ll:116830491:A:T, ll:116830530:T:C, ll:116830568:A:G, ll:116830616:C:CT, ll:116830637:C:T, ll:116830638:G:A, ll:116830897:G:T, 11:116832769:G:A, ll:116832770:G:A, 11:116832882:T:G, ll:116830535:AC:A, ll:116830897:G:A, ll:116830898:T:A, 11:116832768:TG:T, 11:116832882:T:A, ll:116830491:A:C, ll:116830531:G:T, ll:116830542:GT:G, ll:116830584:T:C, ll:116830584:T:G, ll:116830638:G:T, ll:116830771:A:G, ll:116830868:C:T, ll:116830886:C:T, ll:116832805:G:A, 11:116832879:GCCTGAGA:G, ll:116830772:G:T, and 11:116832799:AC:A.

26. The method of any one of claims 23 to 25, further comprising administering an APOC3 therapeutic agent in an amount that is the same as or less than a standard dosage amount or an aneurysm therapy, and / or an APOC3 inhibitor to a subject that is APOC3 reference.

27. The method of claim 26, wherein the subject is APOC3 reference, and the subject is administered or continued to be administered the aneurysm therapeutic agent in an amount that is the same as or less than a standard dosage amount or an aneurysm therapy, and the APOC3 inhibitor.

28. The method of any one of claims 23 to 25, further comprising administering an APOC3 therapeutic agent in an amount that is the same as or less than a standard dosage amount oran aneurysm therapy, and / or an APOC3 inhibitor to a subject that is heterozygous for an APOC3 variant nucleic acid molecule.

29. The method of claim 28, wherein the subject is heterozygous for the APOC3 variant nucleic acid molecule, and the subject is administered or continued to be administered the aneurysm therapeutic agent in an amount that is the same as or less than a standard dosage amount or an aneurysm therapy, and the APOC3 inhibitor.

30. The method of any one of claims 23 to 29, wherein the APOC3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an APOC3 nucleic acid molecule.

31. The method of claim 30, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), and / or a short hairpin RNA (shRNA).

32. The method of claim 31, wherein the inhibitory nucleic acid molecule comprises an siRNA.

33. The method of claim 31, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule.

34. An aneurysm therapeutic agent for use in treating an aneurysm, preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm in a subject having an APOC3 variant nucleic acid molecule.

35. The aneurysm therapeutic agent of claim 34, wherein the APOC3 variant nucleic acid molecule is a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, a missense variant, an in-frame indel variant, or a variant that encodes a truncated APOC3 variant polypeptide.

36. The aneurysm therapeutic agent of claim 34 or claim 35, wherein the APOC3 variant nucleic acid molecule comprises one or more of the genetic variations ll:116830491:A:T, ll:116830530:T:C, ll:116830568:A:G, ll:116830616:C:CT, ll:116830637:C:T, ll:116830638:G:A, ll:116830897:G:T, 11:116832769:G:A, ll:116832770:G:A, 11:116832882:T:G, ll:116830535:AC:A, ll:116830897:G:A, ll:116830898:T:A, 11:116832768:TG:T, 11:116832882:T:A, ll:116830491:A:C, ll:116830531:G:T, ll:116830542:GT:G, ll:116830584:T:C, ll:116830584:T:G, ll:116830638:G:T, ll:116830771:A:G, ll:116830868:C:T, ll:116830886:C:T, ll:116832805:G:A, 11:116832879:GCCTGAGA:G, ll:116830772:G:T, and 11:116832799:AC:A.

37. An Apolipoprotein C3 (APOC3) inhibitor for use in treating an aneurysm, preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm in a subject that is APOC3 reference or is heterozygous for an APOC3 variant nucleic acid molecule.

38. The APOC3 inhibitor of claim 37, wherein the APOC3 variant nucleic acid molecule is a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, a missense variant, an in-frame indel variant, or a variant that encodes a truncated APOC3 variant polypeptide.

39. The APOC3 inhibitor of claim 37 or claim 38, wherein the APOC3 variant nucleic acid molecule comprises one or more of the genetic variations ll:116830491:A:T, ll:116830530:T:C, ll:116830568:A:G, ll:116830616:C:CT, ll:116830637:C:T, ll:116830638:G:A, ll:116830897:G:T, 11:116832769:G:A, ll:116832770:G:A, 11:116832882:T:G, ll:116830535:AC:A, ll:116830897:G:A, ll:116830898:T:A, 11:116832768:TG:T, 11:116832882:T:A, ll:116830491:A:C, ll:116830531:G:T, ll:116830542:GT:G, ll:116830584:T:C, ll:116830584:T:G, ll:116830638:G:T, ll:116830771:A:G, ll:116830868:C:T, ll:116830886:C:T, ll:116832805:G:A, 11:116832879:GCCTGAGA:G, ll:116830772:G:T, and 11:116832799:AC:A.

40. The APOC3 inhibitor of any one of claims 37 to 39, wherein the APOC3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an APOC3 nucleic acid molecule.

41. The APOC3 inhibitor of claim 40, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), and / or a short hairpin RNA (shRNA).

42. The APOC3 inhibitor of claim 41, wherein the inhibitory nucleic acid molecule comprises an siRNA.

43. The APOC3 inhibitor of claim 41, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule.

44. A method of treating a subject having an abdominal aortic aneurysm or at risk of developing an abdominal aortic aneurysm, or preventing an abdominal aortic aneurysm, preventing progression of an abdominal aortic aneurysm, or preventing a complication of an abdominal aortic aneurysm, the method comprising administering: a therapeutic agent that decreases low-density lipoprotein (LDL); and / ora therapeutic agent that increases high-density lipoprotein (HDL).

45. The method of claim 44, wherein the therapeutic agent that decreases LDL comprises a statin, a Proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitor, a fibrate, a bile acid resin, an omega-3 fatty acid, an adenosine triphosphate-or a citrate lyase (ACL) inhibitor, or any combination thereof.

46. The method of claim 44, wherein the method comprises administering a PCSK9 inhibitor to the subject.

47. The method of claim 46, wherein the PCSK9 inhibitor comprises alirocumab, evolocumab, inclisiran, or bococizumab.

48. The method of claim 46, wherein the PCSK9 inhibitor comprises alirocumab.

49. The method of claim 44, wherein the method comprises administering a PCSK9 inhibitor and an apolipoprotein C3 (APOC3) inhibitor to the subject.

50. The method of claim 44, wherein the method comprises administering a therapeutic agent that decreases LDL and does not comprise administering a therapeutic agent that increases HDL, wherein the therapeutic agent that decreases LDL comprises a statin, a fibrate, a bile acid resin, an omega-3 fatty acid, an adenosine triphosphate-or an ACL inhibitor, or any combination thereof.

51. The method of claim 44, wherein the therapeutic agent that increases HDL comprises niacin, a fibrate, rosuvastatin, pitavastatin, or an omega-3 fatty acid, or any combination thereof.

52. The method of any one of claims 44, 45, and 51, the method further comprising administering an apolipoprotein C3 (APOC3) inhibitor and / or a CETP inhibitor to the subject.

53. The method of claim 49 or claim 52, wherein the APOC3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an APOC3 nucleic acid molecule.

54. The method of claim 53, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), and / or a short hairpin RNA (shRNA).

55. The method of claim 54, wherein the inhibitory nucleic acid molecule comprises an siRNA.

56. The method of claim 54, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule.

57. The method of any one of claims 44 to 56, the method further comprising administering a cholesteryl ester transfer protein (CETP) inhibitor to the subject.

58. The method of claim 57, wherein the CETP inhibitor comprises anacetrapib or obicetrapib, or a combination thereof.

59. A method of treating a subject having an abdominal aortic aneurysm or at risk of developing an abdominal aortic aneurysm, or preventing an abdominal aortic aneurysm, preventing progression of an abdominal aortic aneurysm, or preventing a complication of an abdominal aortic aneurysm, the method comprising administering a cholesteryl ester transfer protein (CETP) inhibitor to the subject.

60. The method of claim 59, wherein the CETP inhibitor comprises anacetrapib or obicetrapib, or a combination thereof.

61. The method of claim 59 or claim 60, the method further comprising administering an apolipoprotein C3 (APOC3) inhibitor to the subject.

62. A therapeutic agent that decreases low-density lipoprotein (LDL) and / or a therapeutic agent that increases high-density lipoprotein (HDL) for use in treating an abdominal aortic aneurysm, preventing an abdominal aortic aneurysm, preventing progression of an abdominal aortic aneurysm, or preventing a complication of an abdominal aortic aneurysm in a subject.

63. The therapeutic agent that decreases LDL of claim 62, wherein the therapeutic agent that decreases LDL comprises a statin, a PCSK9 inhibitor, a fibrate, a bile acid resin, an omega-3 fatty acid, an adenosine triphosphate-or a citrate lyase (ACL) inhibitor, or any combination thereof.

64. The therapeutic agent that increases HDL of claim 62, wherein the therapeutic agent that increases HDL comprises niacin, a fibrate, rosuvastatin, pitavastatin, or an omega-3 fatty acid, or any combination thereof.

65. A cholesteryl ester transfer protein (CETP) inhibitor for use in treating an abdominal aortic aneurysm, preventing an abdominal aortic aneurysm, preventing progression of an abdominal aortic aneurysm, or preventing a complication of an abdominal aortic aneurysm in a subject.

66. The CETP inhibitor of claim 65, wherein the CETP inhibitor comprises anacetrapib or obicetrapib, or a combination thereof.

67. A method of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing acomplication of an aneurysm, the method comprising performing gene editing on a subject that is Apolipoprotein C3 (APOC3) reference or heterozygous for an APOC3 variant nucleic acid molecule, to replace the reference copy of the APOC3 gene with an APOC3 variant nucleic acid molecule.

68. The method of claim 67, wherein the aneurysm is an abdominal aortic aneurysm, a thoracic aortic aneurysm, a cerebral aneurysm, a carotid aneurysm, a popliteal aneurysm, a mesenteric aneurysm, or a splenic aneurysm.

69. The method of claim 67, wherein the aneurysm is an abdominal aortic aneurysm.

70. The method of any one of claims 67 to 69, wherein the subject is also administered an aneurysm therapeutic agent.

71. The method of any one of claims 67 to 70, further comprising detecting the presence or absence of an APOC3 variant nucleic acid molecule in a biological sample from the subject.

72. The method of any one of claims 67 to 71, wherein the APOC3 variant nucleic acid molecule comprises a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, a missense variant, an in-frame indel variant, and / or a variant that encodes a truncated APOC3 variant polypeptide.

73. The method of any one of claims 67 to 72, wherein the APOC3 variant nucleic acid molecule comprises one or more of the genetic variations ll:116830491:A:T, ll:116830530:T:C, ll:116830568:A:G, ll:116830616:C:CT, ll:116830637:C:T, ll:116830638:G:A, ll:116830897:G:T, 11:116832769:G:A, ll:116832770:G:A, 11:116832882:T:G, ll:116830535:AC:A, ll:116830897:G:A, ll:116830898:T:A, 11:116832768:TG:T, 11:116832882:T:A, ll:116830491:A:C, ll:116830531:G:T, ll:116830542:GT:G, ll:116830584:T:C, ll:116830584:T:G, ll:116830638:G:T, ll:116830771:A:G, ll:116830868:C:T, ll:116830886:C:T, ll:116832805:G:A, 11:116832879:GCCTGAGA:G, ll:116830772:G:T, and 11:116832799:AC:A.

74. A method of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, the method comprising performing gene editing on a subject that is Proprotein Convertase Su btil isi n / Kexin type 9 (PCSK9) reference or heterozygous for a PCSK9 variant nucleic acid molecule, to replace the reference copy of the PCSK9 gene with a PCSK9 variant nucleic acid molecule.

75. The method of claim 74, wherein the aneurysm is an abdominal aortic aneurysm, a thoracic aortic aneurysm, a cerebral aneurysm, a carotid aneurysm, a popliteal aneurysm, a mesenteric aneurysm, or a splenic aneurysm.

76. The method of claim 74, wherein the aneurysm is an abdominal aortic aneurysm.

77. The method of any one of claims 74 to 76, wherein the subject is also administered an aneurysm therapeutic agent.

78. The method of any one of claims 74 to 77, further comprising detecting the presence or absence of a PCSK9 variant nucleic acid molecule in a biological sample from the subject.

79. The method of any one of claims 74 to 78, wherein the PCSK9 variant nucleic acid molecule comprises a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, a missense variant, an in-frame indel variant, and / or a variant that encodes a truncated PCSK9 variant polypeptide.

80. The method of any one of claims 74 to 79, wherein the PCSK9 variant nucleic acid molecule comprises one or more of the genetic variations l:55039839:T:A, l:55039895:C:G, l:55039916:G:T, l:55039952:G:A, l:55039971:T:C, l:55039973:C:T, l:55039977:C:G, l:55039979:G:A, l:55039997:GA:G, l:55040000:GCACCC:G, l:55040034:G:T, l:55043847:C:T, l:55043857:G:T, l:55043870:G:A, l:55043871:T:C, l:55043873:G:T, l:55043901:C:G, l:55043912:C:T, l:55043922:G:A, l:55043924:C:T, l:55043925:G:A, l:55043933:G:A, l:55043945:C:T, l:55043946:G:A, l:55043948:C:T, l:55043972:C:T, l:55043996:G:A, l:55044010:G:C, l:55044017:G:A, l:55044020:G:A, l:55044035:G:A, l:55046524:C:A, l:55046544:G:A, l:55046553:G:A, l:55046587:C:T, l:55046601:C:T, l:55046602:G:A, l:55046610:C:A, l:55046640:C:T, l:55046644:C:T, l:55046647:G:A, l:55052295:G:C, l:55052307:C:G, l:55052371:A:G, l:55052380:C:A, l:55052382:G:A, l:55052391:G:A, l:55052409:C:G, l:55052651:C:A, l:55052666:G:C, l:55052677:C:T, l:55052697:C:A, l:55052698:G:A, l:55052701:C:T, l:55052713:G:A, l:55052734:C:T, l:55052735:G:A, l:55052753:A:T, l:55052771:C:T, l:55052791:G:A, l:55055999:A:T, l:55056019:C:A, l:55056040:C:A, l:55056056:C:T, l:55056085:A:G, l:55056151:G:A, l:55056154:G:A, l:55057329:A:G, l:55057340:G:A, l:55057374:C:T, l:55057403:C:T, l:55057407:G:A, l:55057410:T:G, l:55057433:G:C, l:55057436:A:G, l:55057454:G:A, l:55057464:C:T, l:55057468:C:G, l:55057475:T:C, l:55057475:TCA:T, l:55057508:G:A, l:55057514:G:A, l:55058066:C:T, l:55058096:G:T, l:55058156:G:A, l:55058188:C:T, l:55058191:C:A, l:55058197:A:ACC, l:55058498:G:T, l:55058516:A:G, l:55058538:C:T, l:55058543:C:G,l:55058549:C:T, l:55058570:C:T, l:55058580:C:T, l:55058617:GA:G, l:55058627:C:T, l:55058630:C:T, l:55058631:G:A, l:55058636:G:T, l:55059489:C:T, l:55059496:G:A, l:55059537:G:A, l:55059538:G:A, l:55059544:A:G, l:55059546:G:A, l:55059586:G:A, l:55059627:C:T, l:55059660:A:G, l:55061485:G:A, l:55061498:A:G, l:55063370:T:G, l:55063460:A:G, l:55063474:A:G, l:55063480:C:T, l:55063485:CG:C, l:55063486:G:A, l:55063487:TCAGCA:T, l:55063543:C:T, l:55063544:G:A, l:55063561:C:T, l:55063582:T:C, l:55039842:G:A, l:55039857:G:T, l:55039926:C:A, l:55039940:G:T, l:55039973:C:T, l:55039979:G:A, l:55039982:G:A, l:55040034:G:A, l:55043847:C:T, l:55043870:G:A, l:55043871:T:C, l:55043901:C:G, l:55043907:C:G, l:55043909:G:A, l:55043912:C:A, l:55043912:C:T, l:55043924:C:T, l:55043925:G:A, l:55043930:C:A, l:55043933:G:A, l:55043945:C:T, l:55043946:G:A, l:55043966:A:T, l:55043973:A:G, l:55043999:T:G, l:55044010:G:C, l:55044017:G:A, l:55046553:G:A, l:55046581:G:A, l:55046585:C:G, l:55046587:C:T, l:55046601:C:T, l:55046602:G:A, l:55046610:C:G, l:55046640:C:G, l:55046646:G:A, l:55046647:G:A, l:55052276:A:G, l:55052307:C:G, l:55052333:C:A, l:55052343:G:A, l:55052370:G:A, l:55052380:C:A, l:55052382:G:A, l:55052397:C:T, l:55052401:T:C, l:55052409:C:G, l:55052698:G:A, l:55052701:C:T, l:55052702:G:A, l:55052707:G:C, l:55052711:G:C, l:55052734:C:T, l:55052735:G:A, l:55052744:G:A, l:55052746:G:A, l:55052758:C:T, l:55052771:C:T, l:55052779:G:A, l:55056028:C:A, l:55056068:G:T, l:55056085:A:G, l:55056087:C:A, l:55056091:G:A, l:55056148:C:T, l:55056149:G:A, l:55056168:C:G, l:55056185:C:T, l:55057340:G:A, l:55057343:G:A, l:55057368:C:T, l:55057392:C:A, l:55057401:GC:G, l:55057403:C:T, l:55057404:G:A, l:55057433:G:C, l:55057439:A:T, l:55057454:G:A, l:55057470:T:C, 1 :55057475 :TCA:T, l:55057512:C:G, l:55058066:C:T, l:55058110:T:G, l:55058127:C:G, l:55058150:A:G, l:55058189:C:T, l:55058191:C:T, l:55058538:C:G, l:55058543:C:G, l:55058549:C:T, l:55058570:C:T, l:55058587:G:C, l:55058590:G:C, l:55058627:C:T, l:55058630:C:T, l:55058631:G:A, l:55058638:G:C, l:55058639:C:T, l:55059492:G:T, l:55059510:C:T, l:55059537:G:A, l:55059538:G:A, l:55059603:C:T, l:55059649:G:T, l:55059660:A:G, l:55061485:G:A, l:55061498:A:G, l:55061501:C:T, l:55061558:T:G, l:55063384:G:A, l:55063450:G:A, l:55063459:A:G, l:55063474:A:G, l:55063480:C:T, l:55063542:C:A, l:55063543:C:T, l:55039845:C:A, l:55039902:T:TG, l:55039903:C:CT, 1:55039910:0:6, l:55039925:G:GCGCA, l:55039926:C:G, l:55039940:G:T, l:55039950:A:G, l:55039959:T:A, l:55039979:G:A, l:55039980:AG:A, l:55039989:GC:G, l:55040034:G:A, l:55043846:C:T,l:55043847:C:T, l:55043849:T:TG, l:55043870:G:T, l:55043901:C:G, l:55043906:T:G, l:55043912:C:T, l:55043915:A:C, l:55043921:C:T, l:55043924:C:T, l:55043925:G:A, l:55043925:G:T, l:55043933:G:A, l:55043945:C:T, l:55043946:G:A, l:55043949:G:A, l:55043951:G:A, l:55043970:T:C, l:55043976:T:C, l:55043987:C:T, l:55044012:T:A, l:55044013:G:A, l:55044020:G:A, l:55046521:A:C, l:55046527:T:C, l:55046535:C:T, l:55046549:C:G, l:55046552:C:G, l:55046570:CTT:C, l:55046587:C:T, l:55046594:C:A, l:55046602:G:A, l:55046610:C:T, l:55046622:C:T, l:55046640:C:T, l:55046643:C:T, l:55052283:G:T, l:55052284:G:A, l:55052310:G:C, l:55052318:C:CAT, l:55052325:A:G, l:55052335:G:A, l:55052358:G:A, l:55052370:G:A, l:55052382:G:A, l:55052391:G:A, l:55052397:C:T, l:55052412:G:T, l:55052648:A:C, l:55052648:A:G, l:55052650:G:A, l:55052651:CCAGCAAGT:C, l:55052689:G:A, l:55052698:G:A, l:55052701:C:T, l:55052702:G:A, l:55052713:G:A, l:55052716:G:A, l:55052717:C:T, l:55052718:CA:C, l:55052734:C:T, l:55052735:G:A, l:55052739:C:A, l:55052746:G:A, l:55052746:GT:G, l:55052749:C:T, l:55052752:A:T, l:55052764:A:T, l:55052771:C:T, l:55052779:G:A, l:55052783:C:A, l:55056028:C:A, l:55056040:C:A, l:55056041:T:G, l:55056056:C:T, l:55056085:A:G, l:55056096:C:A, l:55056100:C:T, l:55056107:C:A, l:55056115:G:T, l:55056133:G:C, l:55056139:G:A, l:55056158:C:T, l:55056170:C:A, l:55057361:G:A, l:55057365:A:G, l:55057403:C:T, l:55057404:G:A, l:55057415:C:T, l:55057433:G:C, l:55057433:G:T, l:55057454:G:A, l:55057467:G:A, l:55057468:C:A, l:55057478:C:T, l:55057482:G:A, l:55057484:G:A, l:55057503:C:T, l:55057505:C:A, l:55057514:G:A, l:55058066:C:T, l:55058102:T:C, l:55058106:C:A, l:55058125:A:G, l:55058128:A:C, l:55058149:G:A, l:55058153:A:G, 1:55058155:0:1, l:55058165:C:A, l:55058206:G:A, l:55058515:C:G, l:55058522:G:A, l:55058528:T:C, l:55058534:C:G, l:55058538:C:T, l:55058541:G:A, l:55058543:C:G, l:55058549:C:T, l:55058550:G:A, l:55058558:A:G, l:55058567:G:A, l:55058570:C:T, l:55058585:G:A, l:55058589:A:G, l:55058619:G:C, l:55058620:T:A, l:55058627:C:T, l:55058628:G:A, l:55058628:G:T, l:55058630:C:T, l:55058631:G:A, l:55058636:G:A, l:55058639:C:T, l:55058640:G:C, l:55059492:G:T, l:55059493:G:A, l:55059510:C:T, l:55059522:G:A, l:55059540:G:A, l:55059546:G:A, 1:55059549 :A:T, l:55059564:C:G, 1:55059583 :G:T, l:55059627:C:T, l:55059661:C:T, l:55061378:G:A, l:55061383:T:G, l:55061437:C:T, l:55061474:C:A, l:55061485:G:A, l:55061548:C:T, l:55061557:G:A, l:55063375:G:A, l:55063384:G:A, l:55063411:A:C, l:55063414:GC:G, l:55063417:C:T, l:55063420:C:G, l:55063421:C:T, l:55063459:A:G,l:55063463:C:T, l:55063465:T:C, l:55063474:A:G, l:55063480:C:T, l:55063483:G:A, l:55063486:G:A, l:55063519:G:A, l:55063527:CG:C, l:55063535:T:C, l:55063542:C:A, l:55063543:C:T, l:55063544:G:A, l:55063570:C:T, l:55063574:A:C, l:55063574:A:T, l:55039890:T:G, 1:55039902 :T:TGC, l:55039910:C:G, l:55039917:G:A, l:55039923:G:C, l:55039925:G:GCGCA, l:55039937:G:A, l:55039940:G:T, l:55039943:G:C, l:55039979:G:A, l:55040006:G:T, l:55040024:AC:A, l:55040038:CG:C, l:55040046:T:C, l:55043854:G:T, l:55043857:G:T, l:55043865:C:T, l:55043870:G:A, l:55043876:GT:G, l:55043901:C:G, l:55043909:G:C, l:55043912:C:T, l:55043915:A:C, l:55043921:C:T, l:55043922:G:A, l:55043924:C:T, l:55043925:G:A, 1 :55043925 :G:T, l:55043933:G:A, 1 :55043945 :C:T, l:55043946:G:A, l:55043948:C:T, l:55043949:G:A, 1:55043949 :G:T, l:55043952:G:T, l:55043976:T:C, l:55044006:T:A, l:55044013:G:A, 1:55044016:7:0, l:55044020:G:A, l:55044026:C:G, l:55044035:G:T, l:55044036:T:C, l:55046521:A:C, l:55046524:C:A, l:55046527:T:C, l:55046531:GT:G, l:55046535:C:T, l:55046547:T:C, l:55046549:C:G, l:55046572:T:C, l:55046577:C:A, l:55046578:A:G, l:55046579:G:C, l:55046587:C:T, l:55046590:G:A, l:55046591:G:A, l:55046594:C:A, l:55046599:A:G, l:55046600:G:T, l:55046601:C:T, l:55046602:G:A, l:55046605:T:C, l:55046608:C:A, l:55046610:C:A, l:55046622:C:T, l:55046639:G:T, l:55046640:C:T, l:55046643:C:T, l:55046646:G:A, l:55046647:G:A, l:55052284:G:A, l:55052300:G:GT, l:55052311:A:G, l:55052317:G:C, l:55052318:C:CAT, l:55052333:C:A, l:55052334:C:T, l:55052335:G:A, l:55052346:G:A, l:55052353:T:C, l:55052356:T:C, l:55052364:G:A, l:55052370:G:A, l:55052380:C:A, l:55052382:G:A, l:55052390:C:G, l:55052391:G:A, l:55052395:C:A, l:55052395:C:T, l:55052397:C:A, l:55052397:C:T, l:55052398:G:A, l:55052409:C:G, l:55052412:G:T, l:55052648:A:C, l:55052654:G:T, l:55052662:G:C, l:55052666:G:A, l:55052672:G:A, l:55052685:AG:A, l:55052689:G:A, l:55052689:G:T, l:55052698:G:A, l:55052701:C:T, l:55052702:G:A, l:55052704:G:GA, l:55052710:G:A, l:55052713:G:A, l:55052732:T:C, l:55052734:C:T, l:55052735:G:A, l:55052739:C:A, l:55052739:C:G, l:55052743:C:A, l:55052743:C:T, l:55052744:G:A, l:55052746:GT:G, l:55052746:G:A, l:55052749:C:T, 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l:55057480:G:C, l:55057481:A:C, l:55057482:G:A, l:55057493:C:T, l:55057496:G:A, l:55057502:G:C, l:55057503:C:T, l:55057505:C:A, l:55057508:G:A, l:55057514:G:A, l:55057515:G:A, l:55058036:G:T, l:55058066:C:T, l:55058075:C:A, l:55058083:G:A, l:55058092:CA:C, l:55058102:T:C, l:55058105:A:G, l:55058106:C:A, 1:55058110:7:6, l:55058111:C:T, l:55058113:GC:G, l:55058119:G:C, l:55058120:A:G, l:55058120:A:T, l:55058125:A:C, l:55058125:A:G, l:55058139:G:A, l:55058144:C:T, l:55058148:G:C, l:55058149:G:A, l:55058153:A:G, l:55058155:C:T, l:55058156:G:A, l:55058158:G:A, l:55058158:G:T, l:55058165:C:A, l:55058165:C:T, l:55058168:C:T, l:55058176:G:A, l:55058176:G:T, l:55058180:C:A, l:55058188:C:T, l:55058189:C:G, l:55058189:C:T, l:55058202:TG:T, l:55058209:G:A, l:55058503:G:A, l:55058503:G:C, l:55058522:G:A, l:55058528:T:C, l:55058534:C:T, l:55058538:C:G, l:55058538:C:T, l:55058541:G:A, l:55058543:C:G, 1:55058549 :C:T, l:55058550:G:A, l:55058567:G:A, l:55058570:C:A, l:55058570:C:T, l:55058571:G:T, l:55058575:C:A, l:55058585:G:A, l:55058589:A:G, l:55058591:C:G, l:55058597:A:AG, l:55058603:T:G, l:55058606:A:G, l:55058619:G:C, l:55058620:TG:T, l:55058620:T:G, l:55058627:C:T, l:55058628:G:A, l:55058628:G:T, l:55058630:C:G, l:55058630:C:T, l:55058631:G:A, l:55058633:G:A, l:55058636:G:A, l:55058637:A:G, l:55058639:C:T, l:55058640:G:C, l:55058643:T:C, l:55058648:G:A, l:55058649:T:C, l:55059491:A:AG, l:55059492:G:T, l:55059494:G:GGGCA, l:55059510:C:T, l:55059511:G:A, l:55059519:A:G, l:55059520:A:G, l:55059522:G:A, l:55059528:G:C, l:55059529:G:T, l:55059538:G:A, l:55059540:G:A, l:55059545:C:A, l:55059546:G:A, l:55059550:T:C, l:55059552:G:A, l:55059560:C:G,l:55059570:C:T, l:55059573:C:T, l:55059583:G:A, l:55059603:C:T, l:55059625:C:A, l:55059627:C:T, l:55059633:C:T, l:55059637:G:A, l:55059655:T:G, l:55059660:A:G, l:55059665:T:C, l:55061373:A:G, l:55061374:G:C, l:55061375:G:A, l:55061381:G:T, l:55061383:T:A, l:55061383:T:G, l:55061384:C:T, l:55061426:T:A, l:55061432:G:C, l:55061435:CA:C, l:55061437:C:T, l:55061455:T:C, l:55061464:C:T, l:55061473:GC:G, l:55061474:C:A, l:55061485:G:A, l:55061492:GC:G, l:55061492:G:A, l:55061494:T:C, l:55061498:A:G, l:55061500:G:A, l:55061517:CA:C, l:55061517:CAA:C, l:55061546:C:G, l:55061548:C:T, 1:55061554:0:0, l:55061557:G:A, l:55063375:G:A, l:55063380:C:CT, l:55063382:G:A, l:55063383:C:G, l:55063384:G:A, l:55063390:G:T, l:55063391:G:A, l:55063406:G:T, l:55063411:A:G, l:55063411:A:T, l:55063420:C:G, l:55063421:C:T, 1:55063433: AC: A, l:55063435:G:T, l:55063439:T:C, l:55063449:C:A, l:55063456:G:C, l:55063456:G:T, l:55063459:A:G, l:55063463:C:T, l:55063465:T:C, l:55063474:A:G, l:55063480:C:T, l:55063483:G:A, l:55063486:G:A, l:55063486:G:T, l:55063488:C:CA, l:55063492:A:C, l:55063508:G:A, l:55063519:G:A, l:55063526:C:T, l:55063532:C:G, l:55063534:A:G, l:55063535:T:C, l:55063542:C:A, l:55063543:C:T, l:55063544:G:A, l:55063556:T:C, l:55063567:T:TC, l:55063570:C:T, l:55063572:G:C, l:55063574:A:T, l:55063582:T:G, l:55039890:T:G, l:55039895:C:A, l:55039905:T:G, l:55039910:C:G, l:55039917:G:A, l:55039937:G:A, l:55039940:G:T, l:55039943:G:T, l:55039973:C:T, l:55039979:G:A, l:55040004:C:A, l:55040007:A:G, l:55040021:G:C, l:55040036:T:C, l:55043847:C:T, l:55043870:G:A, l:55043877:T:A, l:55043888:G:A, l:55043912:C:T, l:55043921:C:T, l:55043922:G:A, l:55043924:C:T, l:55043925:G:A, l:55043925:G:T, l:55043927:C:A, 1 :55043945 :C:T, l:55043948:C:T, l:55043949:G:A, l:55043952:G:T, l:55043963:A:G, l:55043976:T:C, l:55043990:CT:C, l:55043991:T:C, l:55043999:T:A, l:55044013:G:A, l:55044035:G:T, l:55046527:T:C, l:55046535:C:T, l:55046544:G:A, l:55046549:C:G, l:55046553:G:A, l:55046553:G:C, l:55046559:G:A, l:55046590:G:A, l:55046591:G:A, l:55046594:C:A, l:55046601:C:T, l:55046602:G:A, l:55046610:C:T, l:55046622:C:T, l:55046639:GC:G, l:55046643:C:T, l:55052277:G:A, l:55052278:A:T, l:55052284:G:A, l:55052301:T:C, l:55052333:C:A, l:55052334:C:T, l:55052335:G:A, l:55052346:G:A, l:55052356:T:C, l:55052364:G:A, l:55052370:G:A, l:55052376:G:C, l:55052382:G:A, l:55052391:G:A, l:55052409:C:G, l:55052412:G:T, l:55052648:A:C, l:55052651:CCAGCAAGT:C, l:55052662:G:A, l:55052685:AG:A, l:55052689:G:T, l:55052698:G:A, l:55052701:C:T, l:55052701:C:CG, l:55052710:G:A, l:55052713:G:A,l:55052732:T:C, l:55052734:C:T, l:55052735:G:A, l:55052735:G:T, l:55052739:C:A, l:55052743:C:T, l:55052746:GT:G, l:55052746:G:A, l:55052749:C:T, l:55052764:A:T, l:55052771:C:T, l:55052773:G:C, l:55052779:G:A, l:55056009:GA:G, l:55056028:C:A, l:55056029:C:T, l:55056037:C:T, l:55056040:C:A, l:55056062:C:A, l:55056074:G:A, l:55056076:C:T, l:55056095:G:C, l:55056139:G:A, l:55056144:CT:C, l:55056154:G:A, l:55056163:C:T, l:55056182:C:T, l:55056184:C:G, l:55057351:C:CAATG, l:55057364:C:A, l:55057364:C:T, l:55057365:A:G, l:55057374:C:T, l:55057388:G:A, l:55057389:G:A, l:55057403:C:T, l:55057404:G:A, 1 :55057433 :G:C, l:55057433:G:T, l:55057464:C:G, l:55057478:C:T, l:55057499:G:C, l:55057505:C:A, l:55057511:G:A, l:55057514:G:A, l:55057515:G:T, l:55058036:G:T, l:55058066:C:T, l:55058083:G:A, l:55058102:T:C, l:55058106:C:A, l:55058113:GC:G, l:55058125:A:G, l:55058139:G:A, l:55058149:G:A, l:55058155:C:T, l:55058165:C:A, l:55058189:C:G, l:55058209:G:A, l:55058499:G:A, l:55058515:C:G, l:55058522:G:A, l:55058526:G:C, l:55058528:T:C, l:55058534:C:T, l:55058536:C:G, l:55058538:C:T, l:55058541:G:A, l:55058543:C:G, l:55058549:C:T, l:55058570:C:T, l:55058589:A:G, l:55058591:C:G, l:55058620:TG:T, l:55058627:C:T, l:55058628:G:A, l:55058630:C:T, l:55058631:G:A, l:55058636:G:A, l:55058639:C:T, l:55058640:G:C, l:55058640:G:T, l:55058645:G:A, l:55059484:A:C, l:55059492:G:T, l:55059496:G:A, l:55059504:G:T, l:55059531:G:A, l:55059550:T:C, l:55059598:C:T, l:55059603:C:T, 1:55059627:0:7, l:55061388:C:G, l:55061426:T:A, l:55061474:C:A, l:55061485:G:A, l:55061492:G:A, l:55061500:G:A, l:55061501:C:T, l:55061548:C:T, l:55061555:A:C, l:55061557:G:A, l:55063375:G:A, l:55063382:G:C, l:55063391:G:A, l:55063417:C:T, l:55063420:C:G, l:55063457:A:G, l:55063459:A:G, l:55063463:C:T, l:55063465:T:C, l:55063474:A:G, l:55063480:C:T, l:55063486:G:A, l:55063519:G:A, l:55063542:C:A, 1:55063543 :C:T, l:55063544:G:A, l:55063570:C:T, l:55063574:A:C, l:55039841:G:A, l:55039923:G:C, l:55039926:C:G, l:55039940:G:T, l:55040021:G:C, l:55043906:T:G, l:55043912:C:T, l:55043922:G:A, l:55043925:G:A, 1:55043945 :C:T, l:55043946:G:A, l:55043952:G:T, l:55043991:T:C, l:55044020:G:A, l:55046548:A:G, l:55046549:C:G, l:55046552:C:G, l:55046594:C:A, l:55046601:C:T, l:55046602:G:A, l:55046622:C:T, l:55046643:C:T, l:55046647:G:GT, l:55052283:G:T, l:55052318:C:CAT, l:55052335:G:A, l:55052364:G:A, l:55052370:G:A, l:55052408:A:T, l:55052660:G:T, l:55052689:G:A, l:55052689:G:T, l:55052698:G:A, l:55052701:C:T, l:55052706:T:G, l:55052713:G:A, l:55052732:T:C, l:55052734:C:T, l:55052744:G:A, l:55052746:G:A,l:55052746:G:6, l:55052749:C:T, l:55052764:A:T, l:55052767:G:A, l:55052771:C:T, l:55055991:A:G, l:55056028:C:A, l:55056029:C:T, l:55056037:C:A, l:55056037:C:T, l:55056040:C:A, 155056043 :G: A, l:55056056:C:T, l:55056074:G:A, l:55056134:C:T, l:55056139:G:A, l:55056146:T:A, l:55056154:G:A, l:55056170:C:A, l:55056175:G:T, l:55056187:G:A, l:55057329:A:T, 155057351:C:CAATG, 155057368:C:T, 155057386:T:C, l:55057403:6:T, l:55057452:G:T, l:55057499:G:6, l:55057505:6:A, l:55057507:6:G, l:55058083:G:A, 155058106:C:A, 155058113:60:6, l:55058120:A:T, l:55058139:G:A, l:55058149:G:A, l:55058165:C:A, l:55058193:6A6:6, l:55058499:G:A, l:55058522:G:A, l:55058549:C:T, l:55058567:G:A, l:55058589:A:G, 1:55058619:6:6, l:55058620:T6:T, l:55058628:6:T, l:55058639:C:T, 1:55058640:6:6, l:55058640:6:T, l:55059522:6:A, l:55059523:6:6T, l:55059529:6:T, l:55059531:6:A, l:55059625:6:A, l:55059627:6:T, l:55059661:6:T, l:55061474:6:A, 1:55061509:6:6, l:55061548:6:T, l:55061557:6:A, l:55063375:6:A, l:55063384:6:A, 1:55063456:6 :T, l:55063480:6:T, l:55063528:6:T, and l:55063542:6:A.

81. The method of any one of claims 74 to 80, wherein the P6SK9 variant nucleic acid molecule comprises the genetic variation rsll591147 (Arg46Leu).

82. A method of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, the method comprising: determining or having determined whether the subject has an Apolipoprotein 63 (APO63) variant nucleic acid molecule, by: obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising an APO63 variant nucleic acid molecule; and performing or having performed gene editing on a subject that is APO63 reference or heterozygous for the APO63 variant nucleic acid molecule, to replace the reference copy of the APO63 gene with an APO63 variant nucleic acid molecule, wherein the lack of the APO63 variant nucleic acid molecule in the subject indicates the subject has an increased risk of developing an aneurysm.

83. The method of claim 82, wherein the APO63 variant nucleic acid molecule comprises a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshiftvariant, a missense variant, an in-frame indel variant, and / or a variant that encodes a truncated APOC3 variant polypeptide.

84. The method of claim 82 or claim 83, wherein the APOC3 variant nucleic acid molecule comprises one or more of the genetic variations ll:116830491:A:T, ll:116830530:T:C, ll:116830568:A:G, ll:116830616:C:CT, ll:116830637:C:T, ll:116830638:G:A, ll:116830897:G:T, 11:116832769:G:A, ll:116832770:G:A, 11:116832882:T:G, ll:116830535:AC:A, ll:116830897:G:A, ll:116830898:T:A, 11:116832768:TG:T, 11:116832882:T:A, ll:116830491:A:C, ll:116830531:G:T, ll:116830542:GT:G, ll:116830584:T:C, ll:116830584:T:G, ll:116830638:G:T, ll:116830771:A:G, ll:116830868:C:T, ll:116830886:C:T, ll:116832805:G:A, 11:116832879:GCCTGAGA:G, ll:116830772:G:T, and 11:116832799:AC:A.

85. The method of any one of claims 82 to 84, wherein the aneurysm is an abdominal aortic aneurysm, a thoracic aortic aneurysm, a cerebral aneurysm, a carotid aneurysm, a popliteal aneurysm, a mesenteric aneurysm, or a splenic aneurysm.

86. The method of claim 85, wherein the aneurysm is an abdominal aortic aneurysm.

87. A method of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, the method comprising: determining or having determined whether the subject has a Proprotein Convertase Su bti lisi n / Kexi n type 9 (PCSK9) variant nucleic acid molecule, by: obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising a PCSK9 variant nucleic acid molecule; and performing or having performed gene editing on a subject that is PCSK9 reference or heterozygous for the PCSK9 variant nucleic acid molecule, to replace the reference copy of the PCSK9 gene with a PCSK9 variant nucleic acid molecule, wherein the lack of the PCSK9 variant nucleic acid molecule in the subject indicates the subject has an increased risk of developing an aneurysm.

88. The method of claim 87, wherein the PCSK9 variant nucleic acid molecule comprises a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshiftvariant, a missense variant, an in-frame indel variant, and / or a variant that encodes a truncated PCSK9 variant polypeptide.

89. The method of claim 87 or claim 88, wherein the PCSK9 variant nucleic acid molecule comprises one or more of the genetic variations l:55039839:T:A, l:55039895:C:G, l:55039916:G:T, l:55039952:G:A, l:55039971:T:C, l:55039973:C:T, l:55039977:C:G, l:55039979:G:A, l:55039997:GA:G, l:55040000:GCACCC:G, l:55040034:G:T, l:55043847:C:T, l:55043857:G:T, l:55043870:G:A, l:55043871:T:C, l:55043873:G:T, l:55043901:C:G, l:55043912:C:T, l:55043922:G:A, l:55043924:C:T, l:55043925:G:A, l:55043933:G:A, l:55043945:C:T, l:55043946:G:A, l:55043948:C:T, l:55043972:C:T, l:55043996:G:A, l:55044010:G:C, l:55044017:G:A, l:55044020:G:A, l:55044035:G:A, l:55046524:C:A, l:55046544:G:A, l:55046553:G:A, l:55046587:C:T, l:55046601:C:T, l:55046602:G:A, l:55046610:C:A, l:55046640:C:T, l:55046644:C:T, l:55046647:G:A, l:55052295:G:C, l:55052307:C:G, l:55052371:A:G, l:55052380:C:A, l:55052382:G:A, l:55052391:G:A, l:55052409:C:G, l:55052651:C:A, l:55052666:G:C, l:55052677:C:T, l:55052697:C:A, l:55052698:G:A, l:55052701:C:T, l:55052713:G:A, l:55052734:C:T, l:55052735:G:A, l:55052753:A:T, l:55052771:C:T, l:55052791:G:A, l:55055999:A:T, l:55056019:C:A, l:55056040:C:A, l:55056056:C:T, l:55056085:A:G, l:55056151:G:A, l:55056154:G:A, l:55057329:A:G, l:55057340:G:A, l:55057374:C:T, l:55057403:C:T, l:55057407:G:A, l:55057410:T:G, l:55057433:G:C, l:55057436:A:G, l:55057454:G:A, l:55057464:C:T, l:55057468:C:G, l:55057475:T:C, l:55057475:TCA:T, l:55057508:G:A, l:55057514:G:A, l:55058066:C:T, l:55058096:G:T, l:55058156:G:A, l:55058188:C:T, l:55058191:C:A, l:55058197:A:ACC, l:55058498:G:T, l:55058516:A:G, l:55058538:C:T, l:55058543:C:G, l:55058549:C:T, l:55058570:C:T, l:55058580:C:T, l:55058617:GA:G, l:55058627:C:T, l:55058630:C:T, l:55058631:G:A, l:55058636:G:T, l:55059489:C:T, l:55059496:G:A, l:55059537:G:A, l:55059538:G:A, l:55059544:A:G, l:55059546:G:A, l:55059586:G:A, l:55059627:C:T, l:55059660:A:G, l:55061485:G:A, l:55061498:A:G, l:55063370:T:G, l:55063460:A:G, l:55063474:A:G, l:55063480:C:T, l:55063485:CG:C, l:55063486:G:A, l:55063487:TCAGCA:T, l:55063543:C:T, l:55063544:G:A, l:55063561:C:T, l:55063582:T:C, l:55039842:G:A, l:55039857:G:T, l:55039926:C:A, l:55039940:G:T, l:55039973:C:T, l:55039979:G:A, l:55039982:G:A, l:55040034:G:A, l:55043847:C:T, l:55043870:G:A, l:55043871:T:C, l:55043901:C:G, l:55043907:C:G, l:55043909:G:A, l:55043912:C:A, l:55043912:C:T, l:55043924:C:T, l:55043925:G:A, l:55043930:C:A, l:55043933:G:A,l:55043945:C:T, l:55043946:G:A, l:55043966:A:T, l:55043973:A:G, l:55043999:T:G, l:55044010:G:C, l:55044017:G:A, l:55046553:G:A, l:55046581:G:A, l:55046585:C:G, l:55046587:C:T, l:55046601:C:T, l:55046602:G:A, l:55046610:C:G, l:55046640:C:G, l:55046646:G:A, l:55046647:G:A, l:55052276:A:G, l:55052307:C:G, l:55052333:C:A, l:55052343:G:A, l:55052370:G:A, l:55052380:C:A, l:55052382:G:A, l:55052397:C:T, l:55052401:T:C, l:55052409:C:G, l:55052698:G:A, l:55052701:C:T, l:55052702:G:A, l:55052707:G:C, l:55052711:G:C, l:55052734:C:T, l:55052735:G:A, l:55052744:G:A, l:55052746:G:A, l:55052758:C:T, 1:55052771:0:7, l:55052779:G:A, l:55056028:C:A, l:55056068:G:T, l:55056085:A:G, l:55056087:C:A, l:55056091:G:A, l:55056148:C:T, l:55056149:G:A, l:55056168:C:G, l:55056185:C:T, l:55057340:G:A, l:55057343:G:A, l:55057368:C:T, l:55057392:C:A, l:55057401:GC:G, l:55057403:C:T, l:55057404:G:A, l:55057433:G:C, l:55057439:A:T, l:55057454:G:A, l:55057470:T:C, 1:55057475 :TCA:T, l:55057512:C:G, l:55058066:C:T, l:55058110:T:G, l:55058127:C:G, l:55058150:A:G, l:55058189:C:T, l:55058191:C:T, l:55058538:C:G, l:55058543:C:G, l:55058549:C:T, l:55058570:C:T, l:55058587:G:C, l:55058590:G:C, l:55058627:C:T, l:55058630:C:T, l:55058631:G:A, l:55058638:G:C, l:55058639:C:T, l:55059492:G:T, l:55059510:C:T, l:55059537:G:A, l:55059538:G:A, l:55059603:C:T, l:55059649:G:T, l:55059660:A:G, l:55061485:G:A, l:55061498:A:G, l:55061501:C:T, l:55061558:T:G, l:55063384:G:A, l:55063450:G:A, l:55063459:A:G, l:55063474:A:G, l:55063480:C:T, l:55063542:C:A, l:55063543:C:T, l:55039845:C:A, l:55039902:T:TG, l:55039903:C:CT, l:55039910:C:G, l:55039925:G:GCGCA, l:55039926:C:G, l:55039940:G:T, l:55039950:A:G, l:55039959:T:A, l:55039979:G:A, l:55039980:AG:A, l:55039989:GC:G, l:55040034:G:A, l:55043846:C:T, l:55043847:C:T, l:55043849:T:TG, l:55043870:G:T, l:55043901:C:G, l:55043906:T:G, l:55043912:C:T, l:55043915:A:C, l:55043921:C:T, l:55043924:C:T, l:55043925:G:A, l:55043925:G:T, l:55043933:G:A, l:55043945:C:T, l:55043946:G:A, l:55043949:G:A, l:55043951:G:A, l:55043970:T:C, l:55043976:T:C, l:55043987:C:T, l:55044012:T:A, l:55044013:G:A, l:55044020:G:A, l:55046521:A:C, l:55046527:T:C, l:55046535:C:T, l:55046549:C:G, l:55046552:C:G, l:55046570:CTT:C, l:55046587:C:T, l:55046594:C:A, l:55046602:G:A, l:55046610:C:T, l:55046622:C:T, l:55046640:C:T, l:55046643:C:T, l:55052283:G:T, l:55052284:G:A, l:55052310:G:C, l:55052318:C:CAT, l:55052325:A:G, l:55052335:G:A, l:55052358:G:A, l:55052370:G:A, l:55052382:G:A, l:55052391:G:A, l:55052397:C:T, l:55052412:G:T, l:55052648:A:C, l:55052648:A:G, l:55052650:G:A,l:55052651:CCAGCAAGT:C, l:55052689:G:A, l:55052698:G:A, l:55052701:C:T, l:55052702:G:A, l:55052713:G:A, l:55052716:G:A, l:55052717:C:T, l:55052718:CA:C, l:55052734:C:T, l:55052735:G:A, l:55052739:C:A, l:55052746:G:A, l:55052746:GT:G, l:55052749:C:T, l:55052752:A:T, l:55052764:A:T, l:55052771:C:T, l:55052779:G:A, l:55052783:C:A, l:55056028:C:A, l:55056040:C:A, l:55056041:T:G, l:55056056:C:T, l:55056085:A:G, l:55056096:C:A, l:55056100:C:T, l:55056107:C:A, l:55056115:G:T, l:55056133:G:C, l:55056139:G:A, l:55056158:C:T, l:55056170:C:A, l:55057361:G:A, l:55057365:A:G, l:55057403:C:T, l:55057404:G:A, l:55057415:C:T, l:55057433:G:C, l:55057433:G:T, l:55057454:G:A, l:55057467:G:A, l:55057468:C:A, l:55057478:C:T, l:55057482:G:A, l:55057484:G:A, l:55057503:C:T, l:55057505:C:A, l:55057514:G:A, l:55058066:C:T, l:55058102:T:C, l:55058106:C:A, l:55058125:A:G, l:55058128:A:C, l:55058149:G:A, l:55058153:A:G, l:55058155:C:T, l:55058165:C:A, l:55058206:G:A, l:55058515:C:G, l:55058522:G:A, l:55058528:T:C, l:55058534:C:G, l:55058538:C:T, l:55058541:G:A, l:55058543:C:G, l:55058549:C:T, l:55058550:G:A, l:55058558:A:G, l:55058567:G:A, l:55058570:C:T, l:55058585:G:A, l:55058589:A:G, l:55058619:G:C, l:55058620:T:A, l:55058627:C:T, l:55058628:G:A, l:55058628:G:T, l:55058630:C:T, l:55058631:G:A, l:55058636:G:A, l:55058639:C:T, l:55058640:G:C, l:55059492:G:T, l:55059493:G:A, l:55059510:C:T, l:55059522:G:A, l:55059540:G:A, l:55059546:G:A, 1 :55059549 :A:T, 1:55059564:0:6, 1 :55059583 :G:T, l:55059627:C:T, l:55059661:C:T, l:55061378:G:A, l:55061383:T:G, l:55061437:C:T, l:55061474:C:A, l:55061485:G:A, l:55061548:C:T, l:55061557:G:A, l:55063375:G:A, l:55063384:G:A, l:55063411:A:C, l:55063414:GC:G, l:55063417:C:T, l:55063420:C:G, l:55063421:C:T, l:55063459:A:G, l:55063463:C:T, l:55063465:T:C, l:55063474:A:G, l:55063480:C:T, l:55063483:G:A, l:55063486:G:A, l:55063519:G:A, l:55063527:CG:C, l:55063535:T:C, l:55063542:C:A, l:55063543:C:T, l:55063544:G:A, l:55063570:C:T, l:55063574:A:C, l:55063574:A:T, l:55039890:T:G, 1:55039902 :T:TGC, l:55039910:C:G, l:55039917:G:A, l:55039923:G:C, l:55039925:G:GCGCA, l:55039937:G:A, l:55039940:G:T, l:55039943:G:C, l:55039979:G:A, l:55040006:G:T, l:55040024:AC:A, l:55040038:CG:C, l:55040046:T:C, l:55043854:G:T, l:55043857:G:T, l:55043865:C:T, l:55043870:G:A, l:55043876:GT:G, l:55043901:C:G, l:55043909:G:C, l:55043912:C:T, l:55043915:A:C, l:55043921:C:T, l:55043922:G:A, l:55043924:C:T, l:55043925:G:A, 1 :55043925 :G:T, l:55043933:G:A, 1 :55043945 :C:T, l:55043946:G:A, l:55043948:C:T, l:55043949:G:A, 1:55043949 :G:T, l:55043952:G:T,l:55043976:T:C, l:55044006:T:A, l:55044013:G:A, l:55044016:T:G, l:55044020:G:A, l:55044026:C:G, l:55044035:G:T, l:55044036:T:C, l:55046521:A:C, l:55046524:C:A, l:55046527:T:C, l:55046531:GT:G, l:55046535:C:T, l:55046547:T:C, l:55046549:C:G, l:55046572:T:C, l:55046577:C:A, l:55046578:A:G, l:55046579:G:C, l:55046587:C:T, l:55046590:G:A, l:55046591:G:A, l:55046594:C:A, l:55046599:A:G, l:55046600:G:T, l:55046601:C:T, l:55046602:G:A, l:55046605:T:C, l:55046608:C:A, l:55046610:C:A, l:55046622:C:T, l:55046639:G:T, l:55046640:C:T, l:55046643:C:T, l:55046646:G:A, l:55046647:G:A, l:55052284:G:A, l:55052300:G:GT, l:55052311:A:G, l:55052317:G:C, l:55052318:C:CAT, l:55052333:C:A, l:55052334:C:T, l:55052335:G:A, l:55052346:G:A, l:55052353:T:C, l:55052356:T:C, l:55052364:G:A, l:55052370:G:A, l:55052380:C:A, l:55052382:G:A, l:55052390:C:G, l:55052391:G:A, l:55052395:C:A, l:55052395:C:T, l:55052397:C:A, l:55052397:C:T, l:55052398:G:A, l:55052409:C:G, l:55052412:G:T, l:55052648:A:C, l:55052654:G:T, l:55052662:G:C, l:55052666:G:A, l:55052672:G:A, l:55052685:AG:A, l:55052689:G:A, l:55052689:G:T, l:55052698:G:A, l:55052701:C:T, l:55052702:G:A, l:55052704:G:GA, l:55052710:G:A, l:55052713:G:A, l:55052732:T:C, l:55052734:C:T, l:55052735:G:A, l:55052739:C:A, l:55052739:C:G, l:55052743:C:A, l:55052743:C:T, l:55052744:G:A, l:55052746:GT:G, l:55052746:G:A, l:55052749:C:T, l:55052752:A:C, l:55052764:A:T, l:55052768:G:A, l:55052770:A:G, l:55052771:C:T, 1:55052774:1:0, l:55052779:G:A, l:55052783:C:A, l:55052785:C:T, l:55052792:G:GT, l:55056012:A:C, l:55056028:C:A, l:55056040:C:A, l:55056041:T:C, l:55056054:GC:G, l:55056068:G:T, l:55056074:G:A, l:55056076:C:T, l:55056091:G:A, l:55056096:C:A, l:55056121:G:A, l:55056135:T:TGCCG, l:55056139:G:A, l:55056147:C:G, l:55056154:G:A, l:55056162:C:A, l:55056163:C:T, l:55056172:C:A, l:55056184:C:G, l:55057338:C:T, l:55057364:C:A, l:55057364:C:T, l:55057365:A:G, l:55057367:C:T, l:55057368:C:T, l:55057377:TG:T, l:55057388:G:A, l:55057403:C:T, l:55057404:G:A, l:55057404:G:T, l:55057427:G:T, l:55057433:G:C, l:55057454:G:A, l:55057464:C:A, l:55057464:C:G, l:55057466:T:A, l:55057467:G:A, l:55057468:C:A, l:55057468:C:G, l:55057471:T:G, l:55057481:A:C, 1 5057482 :G: A, l:55057484:G:A, l:55057490:T:C, l:55057499:G:C, l:55057505:C:A, l:55057514:G:A, l:55058036:G:T, l:55058066:C:T, l:55058083:G:A, l:55058102:T:C, l:55058106:C:A, l:55058113:GC:G, 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l:55061492:G:A, l:55061494:T:C, l:55061498:A:G, l:55061500:G:A, l:55061517:CA:C, l:55061517:CAA:C, l:55061546:C:G, l:55061548:C:T, l:55061554:C:G, l:55061557:G:A, l:55063375:G:A, l:55063380:C:CT, l:55063382:G:A, l:55063383:C:G, l:55063384:G:A, l:55063390:G:T, l:55063391:G:A, l:55063406:G:T, l:55063411:A:G, l:55063411:A:T, l:55063420:C:G, l:55063421:C:T,1:55063433: AC: A, l:55063435:G:T, l:55063439:T:C, l:55063449:C:A, l:55063456:G:C, l:55063456:G:T, l:55063459:A:G, l:55063463:C:T, l:55063465:T:C, l:55063474:A:G, l:55063480:C:T, l:55063483:G:A, l:55063486:G:A, l:55063486:G:T, l:55063488:C:CA, l:55063492:A:C, l:55063508:G:A, l:55063519:G:A, l:55063526:C:T, l:55063532:C:G, l:55063534:A:G, l:55063535:T:C, l:55063542:C:A, l:55063543:C:T, l:55063544:G:A, l:55063556:T:C, l:55063567:T:TC, l:55063570:C:T, l:55063572:G:C, l:55063574:A:T, l:55063582:T:G, l:55039890:T:G, l:55039895:C:A, l:55039905:T:G, l:55039910:C:G, l:55039917:G:A, l:55039937:G:A, l:55039940:G:T, l:55039943:G:T, l:55039973:C:T, l:55039979:G:A, l:55040004:C:A, l:55040007:A:G, l:55040021:G:C, l:55040036:T:C, l:55043847:C:T, l:55043870:G:A, l:55043877:T:A, l:55043888:G:A, l:55043912:C:T, l:55043921:C:T, l:55043922:G:A, l:55043924:C:T, l:55043925:G:A, l:55043925:G:T, l:55043927:C:A, 1:55043945 :C:T, l:55043948:C:T, l:55043949:G:A, l:55043952:G:T, l:55043963:A:G, l:55043976:T:C, l:55043990:CT:C, l:55043991:T:C, l:55043999:T:A, l:55044013:G:A, l:55044035:G:T, l:55046527:T:C, l:55046535:C:T, l:55046544:G:A, l:55046549:C:G, l:55046553:G:A, l:55046553:G:C, l:55046559:G:A, l:55046590:G:A, l:55046591:G:A, l:55046594:C:A, l:55046601:C:T, l:55046602:G:A, l:55046610:C:T, l:55046622:C:T, l:55046639:GC:G, l:55046643:C:T, l:55052277:G:A, l:55052278:A:T, l:55052284:G:A, l:55052301:T:C, l:55052333:C:A, l:55052334:C:T, l:55052335:G:A, l:55052346:G:A, l:55052356:T:C, l:55052364:G:A, l:55052370:G:A, l:55052376:G:C, l:55052382:G:A, l:55052391:G:A, l:55052409:C:G, l:55052412:G:T, l:55052648:A:C, l:55052651:CCAGCAAGT:C, l:55052662:G:A, l:55052685:AG:A, l:55052689:G:T, l:55052698:G:A, l:55052701:C:T, l:55052701:C:CG, l:55052710:G:A, l:55052713:G:A, l:55052732:T:C, l:55052734:C:T, l:55052735:G:A, l:55052735:G:T, l:55052739:C:A, l:55052743:C:T, l:55052746:GT:G, l:55052746:G:A, l:55052749:C:T, l:55052764:A:T, l:55052771:C:T, l:55052773:G:C, l:55052779:G:A, l:55056009:GA:G, l:55056028:C:A, l:55056029:C:T, l:55056037:C:T, l:55056040:C:A, l:55056062:C:A, l:55056074:G:A, l:55056076:C:T, l:55056095:G:C, l:55056139:G:A, l:55056144:CT:C, l:55056154:G:A, l:55056163:C:T, l:55056182:C:T, l:55056184:C:G, l:55057351:C:CAATG, l:55057364:C:A, l:55057364:C:T, l:55057365:A:G, l:55057374:C:T, l:55057388:G:A, l:55057389:G:A, l:55057403:C:T, l:55057404:G:A, 1 :55057433 :G:C, l:55057433:G:T, l:55057464:C:G, l:55057478:C:T, l:55057499:G:C, l:55057505:C:A, l:55057511:G:A, l:55057514:G:A, l:55057515:G:T, l:55058036:G:T, l:55058066:C:T, l:55058083:G:A, l:55058102:T:C,l:55058106:C:A, l:55058113:GC:G, l:55058125:A:G, l:55058139:G:A, l:55058149:G:A, l:55058155:C:T, l:55058165:C:A, l:55058189:C:G, l:55058209:G:A, l:55058499:G:A, l:55058515:C:G, l:55058522:G:A, l:55058526:G:C, l:55058528:T:C, l:55058534:C:T, l:55058536:C:G, l:55058538:C:T, l:55058541:G:A, l:55058543:C:G, l:55058549:C:T, l:55058570:C:T, l:55058589:A:G, l:55058591:C:G, l:55058620:TG:T, l:55058627:C:T, l:55058628:G:A, l:55058630:C:T, l:55058631:G:A, l:55058636:G:A, l:55058639:C:T, l:55058640:G:C, l:55058640:G:T, l:55058645:G:A, l:55059484:A:C, l:55059492:G:T, l:55059496:G:A, l:55059504:G:T, l:55059531:G:A, l:55059550:T:C, l:55059598:C:T, l:55059603:C:T, l:55059627:C:T, l:55061388:C:G, l:55061426:T:A, l:55061474:C:A, l:55061485:G:A, l:55061492:G:A, l:55061500:G:A, l:55061501:C:T, l:55061548:C:T, l:55061555:A:C, l:55061557:G:A, l:55063375:G:A, l:55063382:G:C, l:55063391:G:A, l:55063417:C:T, l:55063420:C:G, l:55063457:A:G, l:55063459:A:G, l:55063463:C:T, l:55063465:T:C, l:55063474:A:G, l:55063480:C:T, l:55063486:G:A, l:55063519:G:A, l:55063542:C:A, 1 5063543 :C:T, l:55063544:G:A, l:55063570:C:T, l:55063574:A:C, l:55039841:G:A, l:55039923:G:C, l:55039926:C:G, l:55039940:G:T, l:55040021:G:C, l:55043906:T:G, l:55043912:C:T, l:55043922:G:A, l:55043925:G:A, 1 5043945 :C:T, 155043946:G:A, 155043952:G:T, 155043991:T:C, 155044020:G:A, 155046548:A:G, 155046549:C:G, 155046552:C:G, 155046594:C:A, 155046601:C:T, 155046602:G:A, 155046622:C:T, 155046643:C:T, 155046647:G:GT, 155052283:G:T, 155052318:C:CAT, 155052335:G:A, 155052364:G:A, 155052370:G:A, 155052408:A:T, 155052660:G:T, 155052689:G:A, 155052689:G:T, 155052698:G:A, 155052701:C:T, 155052706:T:G, 155052713:G:A, 155052732:T:C, 155052734:C:T, 155052744:G:A, 155052746:G:A, 155052746:G:C, 155052749:C:T, 155052764:A:T, 155052767:G:A, 155052771:C:T, 155055991:A:G, 155056028:C:A, 155056029:C:T, 155056037:C:A, 155056037:C:T, 155056040:C:A, 155056043 :G: A, 155056056:C:T, 155056074:G:A, 155056134:C:T, 155056139:G:A, 155056146:T:A, 155056154:G:A, 155056170:C:A, 155056175:G:T,155056187:G:A, 155057329:A:T, 155057351:C:CAATG, 155057368:C:T, 155057386:T:C, 155057403:C:T, 155057452:G:T, 155057499:G:C, 155057505:C:A, 155057507:C:G, 155058083:G:A, 155058106:C:A, 155058113:60:6, l:55058120:A:T, l:55058139:G:A, l:55058149:G:A, l:55058165:C:A, l:55058193:CAG:C, l:55058499:G:A, l:55058522:G:A, l:55058549:C:T, l:55058567:G:A, l:55058589:A:G, l:55058619:G:C, l:55058620:TG:T, l:55058628:G:T, l:55058639:C:T, l:55058640:G:C, l:55058640:G:T, l:55059522:G:A,l:55059523:C:CT, l:55059529:G:T, l:55059531:G:A, l:55059625:C:A, l:55059627:C:T, l:55059661:C:T, l:55061474:C:A, l:55061509:C:G, l:55061548:C:T, l:55061557:G:A, l:55063375:G:A, l:55063384:G:A, l:55063456:G:T, l:55063480:C:T, l:55063528:G:T, and l:55063542:C:A.

90. The method of claim 87 or claim 88, wherein the PCSK9 variant nucleic acid molecule comprises the genetic variation rsll591147 (Arg46Leu).

91. The method of any one of claims 87 to 90, wherein the aneurysm is an abdominal aortic aneurysm, a thoracic aortic aneurysm, a cerebral aneurysm, a carotid aneurysm, a popliteal aneurysm, a mesenteric aneurysm, or a splenic aneurysm.

92. The method of claim 91, wherein the aneurysm is an abdominal aortic aneurysm.

93. A method of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, the method comprising performing gene editing to disrupt the Lipoprotein(A) (LPA) gene in the subject, wherein the subject comprises an Lp(a) level > 31 mg / dL.

94. The method of claim 93, wherein the aneurysm is an abdominal aortic aneurysm, a thoracic aortic aneurysm, a cerebral aneurysm, a carotid aneurysm, a popliteal aneurysm, a mesenteric aneurysm, or a splenic aneurysm.

95. The method of claim 93, wherein the aneurysm is an abdominal aortic aneurysm.

96. The method of any one of claims 93 to 95, wherein the subject is also administered an aneurysm therapeutic agent.

97. The method of any one of claims 93 to 96, further comprising detecting the amount of Lp(a) in a biological sample from the subject.

98. A method of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, the method comprising: determining or having determined the level of Lipoprotein(A) (LPA) polypeptide in the subject by: obtaining or having obtained a biological sample from the subject; and performing or having performed an assay on the biological sample to determine if the subject has an Lp(a) level > 31 mg / dL; andperforming or having performed gene editing on a subject that has an Lp(a) level > 31 mg / dL to disrupt the LPA gene in the subject; wherein an Lp(a) level > 31 mg / dL indicates the subject has an increased risk of developing an aneurysm.

99. The method of claim 98, wherein the aneurysm is an abdominal aortic aneurysm, a thoracic aortic aneurysm, a cerebral aneurysm, a carotid aneurysm, a popliteal aneurysm, a mesenteric aneurysm, or a splenic aneurysm.

100. The method of claim 98, wherein the aneurysm is an abdominal aortic aneurysm.

101. The method of any one of claims 98 to 100, wherein the subject is also administered an aneurysm therapeutic agent.

102. A method of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, the method comprising performing gene editing to disrupt the Lipoprotein(A) (LPA) gene in the subject, wherein the subject comprises an LPA polygenic risk score (PRS) (LPA PRS) that is greater than the 60% percentile.

103. The method of claim 102, wherein the aneurysm is an abdominal aortic aneurysm, a thoracic aortic aneurysm, a cerebral aneurysm, a carotid aneurysm, a popliteal aneurysm, a mesenteric aneurysm, or a splenic aneurysm.

104. The method of claim 103, wherein the aneurysm is an abdominal aortic aneurysm.

105. The method of any one of claims 102 to 104, wherein the subject is also administered an aneurysm therapeutic agent.

106. The method of any one of claims 102 to 105, further comprising performing an LPA PRS for the subject.

107. A method of treating a subject having an aneurysm or at risk of developing an aneurysm, or preventing an aneurysm, preventing progression of an aneurysm, or preventing a complication of an aneurysm, the method comprising: performing a Lipoprotein(A) (LPA) polygenic risk score (PRS) (LPA PRS) for the subject; and performing gene editing to disrupt the LPA gene in the subject, wherein the subject comprises an LPA PRS that is greater than the 60% percentile; wherein an LPA PRS that is greater than the 60% percentile indicates the subject has an increased risk of developing an aneurysm.

108. The method of claim 117, wherein the aneurysm is an abdominal aortic aneurysm, a thoracic aortic aneurysm, a cerebral aneurysm, a carotid aneurysm, a popliteal aneurysm, a mesenteric aneurysm, or a splenic aneurysm.

109. The method of claim 108, wherein the aneurysm is an abdominal aortic aneurysm.

110. The method of any one of claims 107 to 109, wherein the subject is also administered an aneurysm therapeutic agent.

111. The method of any one of claims 1 to 22, the method further comprising administering an Lipoprotein(A) (LPA) inhibitor to the subject.

112. The method of claim 61, the method further comprising administering a Proprotein convertase su btilisi n / kexi n type 9 (PCSK9) inhibitor to the subject.

113. A method of treating a subject having an abdominal aortic aneurysm or at risk of developing an abdominal aortic aneurysm, or preventing an abdominal aortic aneurysm, preventing progression of an abdominal aortic aneurysm, or preventing a complication of an abdominal aortic aneurysm, the method comprising administering: a Proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitor; and a Lipoprotein(A) (LPA) inhibitor.

114. The method of claim 113, the method further comprising administering a cholesteryl ester transfer protein (CETP) inhibitor to the subject.

115. The therapeutic agent of claim 62, wherein the therapeutic agent comprises an APOC3 inhibitor and / or a CEPT inhibitor.

116. The method of claim 74, wherein the subject has an Lp(a) level >31 mg / dL and or has aLPA GRS in the top 33%.