Therapeutic methods for treating subjects having a risk allele in il33

Abstract

Methods of treating a patient suffering from an interleukin (IL) -33-mediated disorder and methods for determining whether a patient is at increased risk of suffering from an IL-33-mediated disorder or methods for determining whether a patient suffering from a disorder has an increased likelihood of responding to an anti-IL-33 therapy are provided.SOLUTION: A method for treating a patient suffering from asthma, the method comprising administering an IL-33 axis binding antagonist to the patient, wherein the patient's genotype has been determined to comprise at least one allele of a cluster 2 polymorphism defined elsewhere or an equivalent allele at a polymorphism in linkage disequilibrium therewith.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 988,993, filed March 13, 2020, the contents of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to methods of treating patients suffering from interleukin (IL)-33 mediated disorders and methods for determining whether a patient is at increased risk for suffering from an IL-33 mediated disorder or whether a patient suffering from a disorder has an increased likelihood of responding to anti-IL-33 therapy. [Background technology]

[0003] Interleukin-33 (IL-33) is a member of the interleukin-1 (IL-1) cytokine family, encoded by the IL33 gene. IL-33 is constitutively expressed in multiple cell types, including structural cells such as smooth muscle cells, epithelial cells, and endothelial cells. IL-33 expression has also been reported to be induced by inflammatory factors in macrophages and dendritic cells. Cellular stress and mechanical damage caused by environmental triggers, such as allergens, toxins, and pathogens, can lead to the release of IL-33. Free IL-33 associates with the heterodimeric IL-33 receptor complex, which consists of the tumor suppressor 2 (ST2) protein and the interleukin-1 receptor accessory protein (IL-1 RAcP), and activates the AP-1 and NF-κB pathways via the adaptor proteins myeloid differentiation primary response 88 (MyD88) and, potentially, the MyD88 adaptor-like (Mal) protein. IL-33 stimulates multiple cell types, including type II innate lymphoid cells (ILC2s), mast cells, basophils, eosinophils, and dendritic cells, to promote immune responses.

[0004] More recently, IL-33 has been found to exist in both reduced (red-IL-33) and oxidized (ox-IL-33) forms. Red-IL33 exists in serum with a half-life of approximately 4 hours before oxidation. Free red-IL-33 signals through the ST2 pathway, whereas ox-IL33 does not. Conversely, ox-IL33 binds to the receptor for advanced glycation end products (RAGE), whereas red-IL-33 does not. Ox-IL33-dependent RAGE signaling has been shown to inhibit epithelial cell proliferation and migration. Inhibition of IL-33 / RAGE-mediated signaling can enhance epithelial migration, suggesting that inhibition of ox-IL33 signaling may be beneficial for promoting tissue repair and wound healing, for example, by enhancing repair of damaged epithelial barriers.

[0005] Therefore, considering the biological roles of red-IL-33 and ox-IL-33 and the pathological consequences of aberrant IL-33 signaling, IL-33 is an attractive target for the treatment of numerous diseases. Of particular interest, genome-wide association studies (GWAS) have identified common genetic variants in interleukin-33 (IL33) associated with traits including asthma, nasal polyps, and allergic rhinitis, and / or in IL1RL1 (the gene encoding ST2) associated with asthma and eczema (e.g., atopic dermatitis).

[0006] There remains a significant unmet clinical need in many diseases associated with IL-33 signaling. For example, corticosteroid-resistant asthma remains common, and biologic therapies for severe asthma, such as anti-IL-5 drugs, do not work well in all patients. Available evidence suggests that different asthma endotypes are caused by distinct pathological mechanisms. IL-33 signaling may be particularly important in some asthma endotypes but not in others. Similarly, it is likely that IL-33 signaling may be important in specific endotypes of other inflammatory diseases, such as COPD, asthma-COPD overlap (ACO), and atopic dermatitis. Summary of the Invention [Problem to be solved by the invention]

[0007] Therefore, there remains a need in the art to distinguish which disease endotypes IL-33 significantly contributes to or is most likely to cause disease pathology, and to more accurately identify patients with IL33 dominant disease phenotypes. Effective patient selection strategies may enable targeted therapeutic strategies and lead to improved patient outcomes. [Means for solving the problem]

[0008] The present disclosure relates to methods of treating a patient suffering from an interleukin (IL)-33 mediated disorder and methods of determining whether a patient is at increased risk for suffering from an IL-33 mediated disorder.

[0009] In one aspect, a method is provided for treating a subject suffering from an IL-33-mediated disorder, comprising administering to the subject an IL-33 axis binding antagonist, wherein the patient's genotype has been determined to include at least one allele of a Cluster 2 polymorphism as defined in Table 1, or an equivalent allele at a polymorphism in linkage disequilibrium therewith.

[0010] In another aspect, provided is a method for determining whether a patient suffering from an IL-33-mediated disorder is likely to respond to a treatment comprising an IL-33 axis binding antagonist, the method comprising: (a) determining, in a sample from the patient, the genotype of at least one Cluster 2 polymorphism as defined in Table 1, or an equivalent allele at a polymorphism in linkage disequilibrium therewith; and (b) identifying the patient as likely to respond to a treatment comprising an IL-33 axis binding antagonist based on the genotype, wherein the presence of at least one allele of a Cluster 2 polymorphism, or an equivalent allele at a polymorphism in linkage disequilibrium therewith, indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0011] In another aspect, there is provided a method for determining whether a patient has an increased risk of an IL-33 mediated disorder, the method comprising identifying from a sample obtained from the patient a genotype for at least one Cluster 2 polymorphism as defined in Table 1, or an equivalent allele at a polymorphism in linkage disequilibrium therewith, wherein the patient is at increased risk of an IL-33 mediated disorder if the patient's genotype comprises at least one Cluster 2 polymorphism as defined in Table 1, or an equivalent allele at a polymorphism in linkage disequilibrium therewith.

[0012] In another aspect, a method is provided for treating a subject suffering from an IL-33-mediated disorder, comprising administering to the subject an IL-33 axis binding antagonist, wherein the patient's genotype has been determined to include at least one allele of a Cluster 3 polymorphism as defined in Table 2, or an equivalent allele at a polymorphism in linkage disequilibrium therewith.

[0013] In another aspect, provided is a method for determining whether a patient suffering from an IL-33-mediated disorder is likely to respond to a treatment comprising an IL-33 axis binding antagonist, the method comprising: (a) determining, in a sample from the patient, the genotype of at least one Cluster 3 polymorphism as defined in Table 2, or an equivalent allele at a polymorphism in linkage disequilibrium therewith; and (b) identifying the patient as likely to respond to a treatment comprising an IL-33 axis binding antagonist based on the genotype, wherein the presence of at least one allele of a Cluster 3 polymorphism, or an equivalent allele at a polymorphism in linkage disequilibrium therewith, indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0014] In another aspect, there is provided a method for determining whether a patient has an increased risk of an IL-33 mediated disorder, the method comprising identifying from a sample obtained from the patient a genotype for at least one Cluster 3 polymorphism as defined in Table 2, or an equivalent allele at a polymorphism in linkage disequilibrium therewith, wherein the patient is at increased risk of an IL-33 mediated disorder if the patient's genotype comprises at least one Cluster 3 polymorphism as defined in Table 2, or an equivalent allele at a polymorphism in linkage disequilibrium therewith.

[0015] In another aspect, a method is provided for treating a subject suffering from an IL-33-mediated disorder, comprising administering to the subject an IL-33 axis binding antagonist, wherein the patient's genotype has been determined to include at least one allele of a Cluster 1 polymorphism as defined in Table 3, or an equivalent allele at a polymorphism in linkage disequilibrium therewith.

[0016] In another aspect, provided is a method for determining whether a patient suffering from an IL-33-mediated disorder is likely to respond to a treatment comprising an IL-33 axis binding antagonist, the method comprising: (a) determining, in a sample from the patient, the genotype of at least one Cluster 1 polymorphism as defined in Table 3, or an equivalent allele of a polymorphism in linkage disequilibrium therewith; and (b) identifying the patient as likely to respond to a treatment comprising an IL-33 axis binding antagonist based on the genotype, wherein the presence of at least one allele of a Cluster 1 polymorphism, or an equivalent allele of a polymorphism in linkage disequilibrium therewith, indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0017] In another aspect, there is provided a method for determining whether a patient has an increased risk of an IL-33 mediated disorder, the method comprising identifying from a sample obtained from the patient a genotype for at least one Cluster 1 polymorphism as defined in Table 3, or an equivalent allele at a polymorphism in linkage disequilibrium therewith, wherein the patient is at increased risk of an IL-33 mediated disorder if the patient's genotype comprises at least one Cluster 1 polymorphism as defined in Table 3, or an equivalent allele at a polymorphism in linkage disequilibrium therewith.

[0018] In another aspect, a composition is provided comprising an IL-33 axis binding antagonist for use in treating a subject having an IL-33-mediated disorder, wherein the genotype of the subject to be treated has been determined to include at least one allele of a Cluster 2 polymorphism as defined in Table 1, or an equivalent allele at a polymorphism that is in linkage disequilibrium with a Cluster 2 polymorphism as defined in Table 1.

[0019] In another aspect, there is provided the use of an IL-33 axis binding antagonist in the manufacture of a medicament for use in treating a subject suffering from an IL-33 mediated disorder, wherein the genotype of the subject to be treated has been determined to include at least one allele of a Cluster 2 polymorphism as defined in Table 1, or an equivalent allele of a polymorphism that is in linkage disequilibrium with a Cluster 2 polymorphism as defined in Table 1.

[0020] In another aspect, a composition is provided comprising an IL-33 axis binding antagonist for use in treating a subject having an IL-33-mediated disorder, wherein the genotype of the subject to be treated has been determined to include at least one allele of a Cluster 3 polymorphism as defined in Table 2, or an equivalent allele at a polymorphism that is in linkage disequilibrium with a Cluster 3 polymorphism as defined in Table 2.

[0021] In another aspect, there is provided the use of an IL-33 axis binding antagonist in the manufacture of a medicament for use in treating a subject suffering from an IL-33 mediated disorder, wherein the genotype of the subject to be treated has been determined to include at least one allele of a Cluster 3 polymorphism as defined in Table 2, or an equivalent allele at a polymorphism that is in linkage disequilibrium with a Cluster 3 polymorphism as defined in Table 2.

[0022] In another aspect, a composition is provided comprising an IL-33 axis binding antagonist for use in treating a subject having an IL-33-mediated disorder, wherein the genotype of the subject to be treated has been determined to include at least one allele of a Cluster 1 polymorphism as defined in Table 3, or an equivalent allele of a polymorphism that is in linkage disequilibrium with a Cluster 1 polymorphism as defined in Table 3.

[0023] In another aspect, there is provided the use of an IL-33 axis binding antagonist in the manufacture of a medicament for use in treating a subject suffering from an IL-33 mediated disorder, wherein the genotype of the subject to be treated has been determined to comprise at least one allele of a Cluster 1 polymorphism as defined in Table 3, or an equivalent allele of a polymorphism that is in linkage disequilibrium with a Cluster 1 polymorphism as defined in Table 3.

[0024] Examples of the present disclosure will now be described, by way of example only, with reference to the following figures: [Brief explanation of the drawings]

[0025] [Figure 1]Distribution of subjects in the UK Biobank as a function of IL33 pathway risk score (top panel) and logistic regression results for asthma risk as a function of risk score (bottom panel) are shown. [Figure 2] Figure 1 shows a comparison of odds ratios (ORs) associated with a loss-of-function (LoF) rare splice variant in IL33 (rs146597587) in two extreme asthma risk groups based on IL33 pathway gene scores. [Figure 3] Figure 1 shows a comparison of odds ratios (ORs) associated with a loss-of-function rare splice variant in IL33 (rs146597587) in two extreme asthma risk groups based on a genetic risk score based on a set of different asthma risk genes (ORMDL3, ADAM33, TSLP). [Figure 4] Figure 1 shows a density plot of age at onset of asthma between carriers and non-carriers of the IL33 LoF rare variant rs146597587. The shaded area defines the age at onset below which is considered early onset. [Figure 5] Figure 1 shows the clustering of correlations (i.e., common variant coexistence scores) of 39 IL33 common variants in the UK Biobank population identified as asthma risk variants. The plot shows the identification of three clusters (clusters 1, 2, and 3) in which variants coexist with high inter-correlation. Grayscale bars indicate Pearson correlation coefficients. Only positive correlations are shown, with darker shading indicating higher correlations. [Figure 6] It shows that many of the variants in clusters 1, 2, and 3 are found in regions with known transcription factor binding sites. [Figure 7] Figure 3 shows 39 common variants and their association with asthma and age at onset. The -log10 (Bonferroni P value) indicates the statistical significance of the association, with a larger -log10(P) indicating higher significance. The dashed red line indicates a p-value of 0.05. [Figure 8]Logistic regression of rs928413 allele scores and association with asthma risk are shown. The coded allele G increases IL33 expression in the GTEx dataset. The number and frequency of genotypes in the UKBB dataset are shown in boxes next to each estimate. [Figure 9] Figure 1 shows that a selection of SNPs within segment 11 (rs1929995-C, rs1475658-T, and rs13298116-T) associated with increased odds ratios for asthma can significantly modulate the level of expression driven by the IL-33 promoter. % activity is normalized to wild-type segment 11 expression levels. * means p<0.05, *** means p<0.001, and **** means p<0.0001. [Figure 10] Figure 1 shows that a selection of SNPs within segment 13 (rs144829310-T, rs7046661-C, and rs992969-A) associated with increased odds ratios for asthma can significantly modulate the level of expression driven by the IL-33 promoter. % activity is normalized to wild-type segment 13 expression levels. * means p<0.05, *** means p<0.001, and **** means p<0.0001. [Figure 11] Figure 1 shows that rs7038893-C significantly regulates the level of expression driven by the IL-33 promoter. The % activity is normalized to the expression level of the segment containing the wild-type allele at rs7038893. * indicates p<0.05. [Figure 12](a) Polymorphism rs7032572-G, (b) Polymorphism rs10815363-T, (c) Polymorphism rs552376976-T, (d) Polymorphism rs62558407-T, (e) Polymorphism rs13 291323-C, (f) polymorphism rs1475658-T, (g) polymorphism rs13298116-T, (h) polymorphism rs10975481-G, (i) polymorphism rs144829310-T, ( (j) IL-33 expression profiles of U-BIOPRED nasal swab samples from subjects with 0 (no risk), 1 (heterozygous), or 2 (risk) active inducing alleles of polymorphisms rs7046661-C, (k) rs992969-A, (l) rs10975488-G, (m) rs928413-G, or (n) (m) rs7038893-C. The association between each active inducing allele and IL-33 was tested using linear regression with age and sex as covariates. DETAILED DESCRIPTION OF THE INVENTION

[0026] General definition As used herein, "IL-33" protein refers to interleukin-33, specifically mammalian interleukin-33 protein, e.g., the human protein deposited under UniProt number 095760. This entity is not a single species but exists in several forms with different functional activities, e.g., full-length and proteolytically processed forms or oxidized and reduced forms (Cohen et al., 2015 Nat Comm 6:8327; Scott et al., 2018 Sci Rep 8:3363). Given that the reduced form is rapidly oxidized in vivo and in vitro, references to IL-33 in the prior art generally may most likely refer to the detection of the oxidized form. The terms "IL-33," as well as "IL-33 polypeptide" and "IL-33 protein," are used interchangeably. In certain instances, IL-33 is a full-length (FL) protein. In other instances, IL-33 is a mature, proteolytically processed form of IL-33. Recent studies suggest that FL IL-33 has some activity (Cayrol and Girard, Proc Natl Acad Sci USA 106(22):9021-6(2009); Hayakawa et al., Biochem Biophys Res Commun. 387(1):218-22(2009); Scott et al., 2018 Sci Rep 8:3363; Talabot-Ayer et al., J Biol Chem. 284(29):19420-6(2009)). However, N-terminally processed IL-33, including but not limited to aa 72-270, 79-270, 95-270, 99-270, 107-270, 109-270, 111-270, and 112-270, have enhanced activity (Lefrancais 2012, 2014; Scott et al., 2018 Sci Rep 8:3363). In another example, IL-33 can include full-length IL-33, fragments thereof, or IL-33 mutant or variant polypeptides, where a fragment of IL-33 or an IL-33 variant polypeptide retains some or all of the functional properties of active IL-33.

[0027] The terms "interleukin-1 receptor-like 1 (IL1RL1)" and "ST2," used interchangeably herein, refer to any native ST2 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. ST2 is also referred to in the art as DER4, T1, and FIT-1. The term encompasses "full-length," unprocessed ST2 and any form of ST2 resulting from intracellular processing. At least four isoforms of ST2 are known in the art, including a soluble form (sST2, also known as IL1RL1-a) and a transmembrane form (ST2L, also known as IL1RL1-b) resulting from differential mRNA expression from a dual promoter system, and ST2V and ST2LV resulting from alternative splicing. The domain structure of ST2L includes three extracellular immunoglobulin-like C2 domains, a transmembrane domain, and a cytoplasmic Toll / interleukin-1 receptor (TIR) ​​domain. sST2 lacks the transmembrane and cytoplasmic domains contained within ST2L and contains a unique nine-amino acid (aa) C-terminal sequence (see, e.g., Kakkar et al. Nat. Rev. Drug Disc. 40 7:827-840, 2008). sST2 may function as a decoy receptor for inhibiting soluble IL-33. This term also encompasses naturally occurring variants of ST2, such as splice variants (e.g., ST2V, which lacks the third immunoglobulin motif and has a unique hydrophobic tail, and ST2LV, which lacks the transmembrane domain of ST2L) or allelic variants (e.g., variants that protect against or confer asthma risk, as described herein). An exemplary amino acid sequence of human ST2 can be found, for example, in UniProtKB Accession No. 001638. ST2 is part of the IL-33 receptor together with the coreceptor protein IL-1 RAcP.Binding of IL-33 to ST2 and the coreceptor interleukin-1 receptor accessory protein (IL-1 RAcP) forms a 1:1:1 ternary signaling complex, promoting downstream signaling (Lingel et al. Structure 17(10):1398-1410, 2009 and Liu et al. Proc. Nat. Acad. Sci. 11 0(37):14918-14924, 2013).

[0028] In some examples, the IL-33 mediated inflammatory disease can be any of asthma, sepsis, septic shock, atopic dermatitis, allergic rhinitis, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), asthma, COPD overlap syndrome (ACOS), chronic bronchitis, emphysema, chronic rhinosinusitis (with or without nasal polyps), vasculitis, GvHD, uveitis, chronic spontaneous urticaria, sinusitis, or pancreatitis.

[0029] In some examples, the IL-33-mediated disorder is asthma. In some examples, the IL-33-mediated disorder is adult asthma. In some examples, the IL-33-mediated disorder is early-onset asthma. As defined herein, "early-onset" asthma refers to a subject diagnosed with asthma before the age of 25, preferably before the age of 18. The diagnosis may be made by a clinician, for example, using any one of many well-known methods for diagnosing asthma. It should be understood that the methods disclosed herein for use in patients suffering from early-onset asthma are not limited to subjects under the age of 18. For example, the methods may be used on adults (defined herein as 18 years or older), who have had asthma since before the age of 18.

[0030] In some examples, the asthma can be mild asthma, moderate asthma, severe asthma, noneosinophilic asthma, hypoeosinophilic asthma, and hypereosinophilic asthma.

[0031] The terms "mild asthma" and "moderate asthma," as used herein, refer to asthma with a Global Initiative for Asthma (GINA) scale of 3 or less, preferably a GINA scale of 2 or 3. The GINA scale measures the severity of asthma based on the following criteria (see "Pocket Guide for Asthma Management and Prevention," Global Initiative for Asthma; 2019):

[0032] The term "severe asthma," as used herein, refers to asthma that requires intensive treatment (e.g., GINA Steps 4 and 5) to maintain good control or asthma in which good control is not achieved despite intensive treatment (GINA, Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma (GINA) December 2012).

[0033] In some examples, the asthma may be hypereosinophilic asthma. The term "hypereosinophilic asthma," as used herein, refers to an asthma patient with a screening blood eosinophil count of 300 cells / μL or greater.

[0034] In some instances, a subject with asthma may have a blood eosinophil count that is not significantly elevated above the baseline level. The baseline level may be the expected blood eosinophil count of a non-asthmatic healthy subject. In some instances, the baseline level may be 200 cells / μL or less. In some instances, the baseline level may be 150 cells / μL or less.

[0035] The term "effective amount" refers to an amount of a drug effective to treat a disease or disorder in a subject or patient, such as a mammal, for example, a human.

[0036] The term "genotype" refers to a description of the alleles of a gene contained in an individual or sample. In the context of this disclosure, no distinction is made between the genotype of an individual and the genotype of a sample derived from that individual. Genotype is typically determined from a sample of diploid cells, although genotype can be determined from a sample of haploid cells, such as sperm cells.

[0037] "IL-33 axis" refers to nucleic acids (e.g., genes or mRNA transcribed from genes) or polypeptides involved in IL-33 signal transduction. For example, the IL-33 axis can include the ligand IL-33, receptors (e.g., ST2 and / or IL-1 RAcP), adaptor molecules (e.g., MyD88), or proteins that associate with the receptor molecule and / or adaptor molecule (e.g., kinases such as interleukin-1 receptor-associated kinase 1 (IRAK1) and interleukin-1 receptor-associated kinase 4 (IRAK4), or E3 ubiquitin ligases such as TNF receptor-associated factor 6 (TRAF6)).

[0038] The term "patient" refers to a human subject for whom diagnosis or treatment is desired. The terms "patient" and "subject" are used interchangeably herein. A patient may be a clinical patient, a clinical trial volunteer, an experimental animal, etc.

[0039] The term "patient suffering from" refers to a patient who exhibits clinical signs of a particular disease, such as, for example, an IL-33 mediated disorder (e.g., asthma, such as early onset asthma).

[0040] A nucleotide position in a genome where multiple sequences are possible in a population is referred to herein as a "polymorphism" or "polymorphic site." A polymorphic site can be, for example, a nucleotide sequence of two or more nucleotides, an inserted nucleotide or nucleotide sequence, a deleted nucleotide or nucleotide sequence, or a microsatellite. A polymorphic site that is two or more nucleotides in length can be 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or more, 20 or more, 30 or more, 50 or more, 75 or more, 100 or more, 500 or more, or about 1000 nucleotides in length, where all or part of the nucleotide sequence differs within the region. A polymorphic site that is one nucleotide in length is referred to herein as a single nucleotide polymorphism (SNP), as described below. When there are two, three, or four alternative nucleotide sequences at a polymorphic site, each nucleotide sequence is referred to as a "polymorphic variant" or "nucleic acid variant." Each possible variant in a DNA sequence is referred to as an "allele." Typically, the first identified allelic form is arbitrarily referred to as the reference form, and other allelic forms are referred to as alternative or variant alleles. A "common" allele is an allele that is predominant in a given population; for example, this allele is present in multiple members of the population at a generally accepted frequency of greater than about 2%. When two polymorphic variants are present, the polymorphic variant that is present in the majority of samples from the population is referred to as the "dominant allele" or "major allele," and the polymorphic variant that is less prevalent in the population is referred to as the "uncommon allele" or "minor allele." An individual who possesses two major alleles or two minor alleles is "homozygous" for the polymorphism. An individual who possesses one major allele and one minor allele is "heterozygous" for the polymorphism. When there is a C / G or A / T SNP, the alleles are ambiguous and depend on the strand used to extract data from the genotyping platform. When these C / G or A / T SNPs are present, each of the C or G nucleotide or the A or T nucleotide may be a risk allele, as determined by correlation of allele frequencies.

[0041] An allele that correlates with an increased risk of a disease or disorder (e.g., an IL-33-mediated disorder such as asthma) or is associated with an odds ratio or relative risk greater than 1 is referred to as a "risk allele" or "effect allele." A "risk allele" or "effect allele" can be a minor allele or a major allele.

[0042] An "equivalent allele" or "surrogate allele," as used herein, is an allele that is expected to behave similarly to the risk allele and has a high rRNA frequency and / or a high rRNA frequency with the risk allele and / or selected SNP as defined herein. 2 This refers to alleles selected based on a high r value (≥ 0.6) and / or a high D' value (≥ 0.6). 2 The value is ≧0.6, ≧0.7, ≧0.8, ≧0.9, or 1.0. In one example, a high D′ value is ≧0.6, ≧0.7, ≧0.8, ≧0.9, or 1.0.

[0043] "Linkage disequilibrium" or "LD," as used herein, refers to alleles at different loci that are not randomly associated, i.e., not associated in proportion to their frequency. When alleles are in positive linkage disequilibrium, the alleles coexist more frequently than expected for their estimated statistical independence. Conversely, when alleles are in negative linkage disequilibrium, the alleles coexist less frequently than expected for their estimated statistical independence. In some instances, an equivalent polymorphism in linkage disequilibrium has a D' value of 0.6 to 0.8 (but not including 0.8) for the polymorphism. In some instances, an equivalent polymorphism in linkage disequilibrium has a D' value of 0.8 or greater.

[0044] As used herein, "odds ratio" or "OR" refers to the ratio of the odds of disease for individuals who have the marker (allele or polymorphism) to the odds of disease in individuals who do not have the marker (allele or polymorphism).

[0045] "Haplotype," as used herein, refers to a group of alleles on a single chromosome that are closely linked enough to be normally inherited as a unit.

[0046] Treatment method Single nucleotide polymorphisms (SNPs) have been associated with an increased risk of IL33-mediated early-onset asthma. Genetic variants in IL33 have not previously been associated with early-onset asthma. Furthermore, individuals with a higher burden of these risk alleles have been found to have a higher disease risk burden. For example, individuals heterozygous for the cluster 2 risk allele rs928413 have a higher associated risk of developing asthma compared to homozygous carriers of non-risk alleles (Figure 8). Additionally, individuals homozygous for the risk allele rs928413 have a higher associated risk of developing asthma compared to heterozygous carriers of the risk allele.

[0047] Surprisingly, the correlation between IL33 risk alleles and early-onset asthma is not solely related to clinically significant increases in blood eosinophil counts (Table 8). It has previously been hypothesized that IL33 causes pathology in atopic asthma models by amplifying type 2 (T2) inflammatory responses. A downstream consequence of IL33 activation of the T2 response is increased local recruitment and activation of eosinophils. The examples suggest that causative risk alleles may not increase IL33-mediated disease risk solely through eosinophil activation. Thus, the data appear to be the first to demonstrate that causative IL33 SNPs may not exclusively cause IL-33-mediated disease via T2 inflammatory mechanisms, particularly in subjects with early-onset asthma (Table 8).

[0048] The data suggest that screening a subject's genotype may also enable screening and identification of subjects with IL33-mediated disorders, including inflammatory disorders such as asthma, particularly early-onset asthma. Being able to identify subjects with IL33-mediated diseases based on their genotype allows for early intervention with IL33-blocking therapies to which they are most likely to respond. In particular, the present disclosure demonstrates the identification of a subgroup of patients with IL33-driven phenotypes who may benefit from anti-IL33-based therapies and who may not previously have been selected as optimal candidates for such therapies (especially if patients had previously been selected for therapies using more traditional IL33-based biomarkers, such as blood eosinophil levels). Thus, the present disclosure potentially provides a precision-based approach for identifying and delivering anti-IL33 therapies to subjects most likely to respond to anti-IL33 therapies.

[0049] Accordingly, the present disclosure provides methods of treating a patient suffering from an IL-33-mediated disorder (e.g., an inflammatory disorder such as asthma, e.g., early-onset asthma). In particular, the methods of treatment disclosed herein comprise administering a therapeutic agent to a patient based on the presence of at least one allele of a Cluster 1, 2, or 3 polymorphism as defined in Tables 1, 2, and 3 in the patient's genome.

[0050] The Examples report that various alleles of the Cluster 1, 2, and 3 polymorphisms may be causative for the onset and / or ongoing pathology of IL-33-mediated disorders such as asthma, e.g., early-onset asthma. Risk allele polymorphisms are clustered based on the high correlation of the alleles (suggesting that polymorphisms within each cluster may be in linkage disequilibrium) (see Figure 5). In other words, each cluster represents a set of "equivalent alleles." A key element of this disclosure is the identification of potentially causative alleles, rather than simply disease-associated alleles. For example, multiple alleles may be associated with an increased risk of asthma, but are not necessarily responsible for the underlying disease. The Examples clearly demonstrate that at least a subset of SNPs within each cluster increase IL-33 expression under various conditions, including increased expression under basal, low-cytokine, and high-cytokine conditions. Thus, the present disclosure is the first to actually identify genetic markers that not only indicate a subject's predisposition to a particular disease, but also indicate that the disease may be caused by polymorphisms that increase expression of the IL-33 gene. Thus, the present disclosure is the first to identify these SNPs as potentially causative of IL-33 mediated diseases such as asthma, including early onset asthma.

[0051] Accordingly, provided herein are methods of treating a patient suffering from an IL33-mediated disorder, comprising administering to the subject an IL-33 axis binding antagonist, wherein the patient's genotype has been determined to include at least one allele of a Cluster 2 polymorphism defined in Table 1, or an equivalent allele at a polymorphism in linkage disequilibrium therewith. In some examples, the patient's genotype includes one, two, three, four, five, six, or seven of the Cluster 2 alleles listed in Table 1.

[0052] [Table 1]

[0053] The "Cluster 2" polymorphisms define allelic polymorphisms in the IL33 genomic region at positions 6193455-6213468 on chromosome 9. Exemplary Cluster 2 polymorphisms are listed in Table 1. As described in the Examples, Cluster 2 polymorphisms are associated with an increased risk (odds ratio (OR)) of asthma. The strongest association was observed for variant rs992969 (OR=1.13 (CI 1.12-1.15), P=2.32×10-73 (see Table 7). The OR given is for individuals homozygous for the non-risk allele compared with those heterozygous. Interestingly, each of the Cluster 2 polymorphisms is associated with an increased risk of early-onset asthma. The association of rs992969 with early onset was OR=1.14 (1.1-1.18), P=7.52×10-20. Surprisingly, the association with early-onset disease was independent of blood eosinophil counts (Table 8), suggesting that IL33-induced early-onset asthma is not solely mediated by high eosinophil counts.

[0054] Cluster 2 polymorphisms are found upstream of the protein-coding region of the IL33 gene, meaning they do not encode amino acid changes in IL33. Therefore, Cluster 2 SNPs do not encode gain-of-function variants of IL33. Therefore, the causative role of SNPs may be regulatory in nature. For example, without wishing to be bound by theory, SNPs may increase the expression level of wild-type IL33 compared to subjects with non-risk polymorphisms. Non-coding genomic regions contain important cis-acting regulatory elements that induce (or repress) gene expression. For example, non-coding regions contain transcription factor binding elements (TFBEs), which can recruit transcriptional repressors or activators. Mutations within TFBEs may affect the strength of binding of these trans-regulatory elements, thereby increasing the expression level of genes with which the TFBEs associate. Therefore, Cluster 2 polymorphisms may contribute to IL-33-induced pathologies by deregulating IL33 expression, leading to increased IL-33 production. This means that aberrant IL-33-mediated signaling is more likely to be induced, triggered by the release of higher concentrations of stored IL-33. This may be particularly relevant to IL-33-mediated disorders in which acute exacerbations are common. Alternatively or additionally, Cluster 2 polymorphisms may result in leaky expression and release of IL-33, which may be relevant when the IL-33-mediated disorder is characterized by chronic symptoms of IL-33 signaling.

[0055] In some examples, the genotype of the patient to be treated is the G allele at polymorphism rs928413 (SEQ ID NO: 43) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; the T allele at polymorphism rs1888909 (SEQ ID NO: 44) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; the A allele at polymorphism rs992969 (SEQ ID NO: 45) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; the T allele at polymorphism rs3939286 (SEQ ID NO: 46) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; It has been determined that the individual contains at least one allele (e.g., 1, 2, 3, 4, 5, 6, or 7) of a polymorphism selected from the group consisting of the C allele at polymorphism rs2381416 (SEQ ID NO: 47) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the A allele at polymorphism rs928412 (SEQ ID NO: 48) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, and the T allele at polymorphism rs7848215 (SEQ ID NO: 49) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith.

[0056] In some examples, the genotype of the patient to be treated has been determined to include at least one allele at a polymorphism selected from the group consisting of a G allele at polymorphism rs928413 (SEQ ID NO: 43), a T allele at polymorphism rs1888909 (SEQ ID NO: 44), an A allele at polymorphism rs992969 (SEQ ID NO: 45), a T allele at polymorphism rs3939286 (SEQ ID NO: 46), a C allele at polymorphism rs2381416 (SEQ ID NO: 47), an A allele at polymorphism rs928412 (SEQ ID NO: 48), and a T allele at polymorphism rs7848215 (SEQ ID NO: 49).

[0057] In some examples, the genotype of the patient to be treated has been determined to include at least one allele of each of the following polymorphisms: a G allele at polymorphism rs928413 (SEQ ID NO: 43), a T allele at polymorphism rs1888909 (SEQ ID NO: 44), an A allele at polymorphism rs992969 (SEQ ID NO: 45), a T allele at polymorphism rs3939286 (SEQ ID NO: 46), a C allele at polymorphism rs2381416 (SEQ ID NO: 47), an A allele at polymorphism rs928412 (SEQ ID NO: 48), and a T allele at polymorphism rs7848215 (SEQ ID NO: 49).

[0058] In some examples, the genotype of the patient to be treated has been determined to include two alleles at polymorphisms selected from two G alleles at polymorphism rs928413 (SEQ ID NO: 43), two T alleles at polymorphism rs1888909 (SEQ ID NO: 44), two A alleles at polymorphism rs992969 (SEQ ID NO: 45), two T alleles at polymorphism rs3939286 (SEQ ID NO: 46), two C alleles at polymorphism rs2381416 (SEQ ID NO: 47), two A alleles at polymorphism rs928412 (SEQ ID NO: 48), and two T alleles at polymorphism rs7848215 (SEQ ID NO: 49).

[0059] In some examples, the genotype of the patient to be treated is two G alleles at polymorphism rs928413 (SEQ ID NO: 43) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith; two T alleles at polymorphism rs1888909 (SEQ ID NO: 44) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith; two A alleles at polymorphism rs992969 (SEQ ID NO: 45) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith; two T alleles at polymorphism rs3939286 (SEQ ID NO: 46) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith; It has been determined that the gene contains two alleles in a polymorphism selected from two equivalent alleles in a polymorphism in linkage disequilibrium with the polymorphism, two C alleles in polymorphism rs2381416 (SEQ ID NO: 47) or two equivalent alleles in a polymorphism in linkage disequilibrium with the polymorphism, two A alleles in polymorphism rs928412 (SEQ ID NO: 48) or two equivalent alleles in a polymorphism in linkage disequilibrium with the polymorphism, and two T alleles in polymorphism rs7848215 (SEQ ID NO: 49) or two equivalent alleles in a polymorphism in linkage disequilibrium with the polymorphism.

[0060] In some examples, the patient's genotype includes at least one G allele at polymorphism rs928413 (SEQ ID NO: 43) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith.

[0061] In some examples, the patient's genotype includes at least one G allele at polymorphism rs928413 (SEQ ID NO: 43).

[0062] In some instances, the patient's genotype includes two G alleles at polymorphism rs928413 (SEQ ID NO: 43) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith.

[0063] In some examples, the patient's genotype includes two G alleles at polymorphism rs928413 (SEQ ID NO: 43).

[0064] Subjects with a genotype having one G allele at the polymorphism rs928413 have been found to have an approximately 14% increased risk of the IL-33-mediated disorder asthma (see Figure 8). Genotypes with two G alleles at the polymorphism rs928413 increase the risk of asthma by approximately 28% in the UKB dataset. The examples also show that the G allele at the polymorphism rs928413 increases expression from the IL-33 promoter under low cytokine conditions.

[0065] In some examples, the patient's genotype includes at least one A allele at polymorphism rs992969 (SEQ ID NO: 45) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith. The Examples show that the A allele at polymorphism rs992969 also increases expression from the IL-33 promoter under low cytokine conditions.

[0066] In some examples, the patient's genotype includes at least one A allele at polymorphism rs992969 (SEQ ID NO: 45).

[0067] In some instances, the patient's genotype comprises two A alleles at polymorphism rs992969 (SEQ ID NO: 45) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith.

[0068] In some examples, the patient's genotype includes two A alleles at polymorphism rs992969 (SEQ ID NO: 45).

[0069] Some additional polymorphisms that are associated with Cluster 2, such as by being in LD with the Cluster 2 polymorphisms listed in Table 1, include:

[0070] [Table 2]

[0071] The Examples show that these polymorphisms increase expression from the IL-33 promoter under basal, low cytokine, and / or high cytokine conditions, suggesting that these SNPs are causative in the pathogenesis of IL-33-mediated disorders.

[0072] In some examples, the genotype of the patient to be treated has been determined to include at least one allele selected from the C allele at polymorphism rs7046661 (SEQ ID NO: 82), the T allele at polymorphism rs10815363 (SEQ ID NO: 83), the T allele at polymorphism rs62558407 (SEQ ID NO: 84), the T allele at polymorphism rs1475658 (SEQ ID NO: 85), and the G allele at polymorphism rs10975481 (SEQ ID NO: 86).

[0073] In some examples, the genotype of the patient to be treated has been determined to include at least one T allele at the polymorphism rs10815363 (SEQ ID NO: 83). In some examples, the genotype of the patient to be treated has been determined to include two T alleles at the polymorphism rs10815363 (SEQ ID NO: 83). The examples show that the T allele at the polymorphism rs10815363 enhances expression from the IL-33 promoter under basal conditions.

[0074] In some examples, the genotype of the patient to be treated has been determined to include at least one T allele at the polymorphism rs1475658 (SEQ ID NO: 85). In some examples, the genotype of the patient to be treated has been determined to include two T alleles at the polymorphism rs1475658 (SEQ ID NO: 85). The examples show that the T allele at the polymorphism rs1475658 enhances expression from the IL-33 promoter under basal conditions.

[0075] In another aspect, methods are provided for treating a subject suffering from an IL-33-mediated disorder, comprising administering to the subject an IL-33 axis-binding antagonist, wherein the patient's genotype has been determined to include at least one allele of a Cluster 3 polymorphism as defined in Table 2, or an equivalent allele at a polymorphism in linkage disequilibrium therewith. In some examples, the patient's genotype includes one, two, three, four, five, six, seven, eight, nine, or ten of the Cluster 3 alleles listed in Table 2.

[0076] [Table 3]

[0077] The "Cluster 3" polymorphisms define allelic polymorphisms in the IL33 genomic region at positions 6172380-6219176 on chromosome 9. As explained in the Examples, Cluster 3 polymorphisms are associated with an increased risk (odds ratio (OR)) of asthma (see Table 7). The OR given is for individuals homozygous for the non-risk allele compared with individuals heterozygous. Interestingly, each of the Cluster 3 polymorphisms is also associated with an increased risk of early-onset asthma that is independent of blood eosinophil counts (Table 8), suggesting that IL33-induced early-onset asthma is not solely mediated by high eosinophil counts.

[0078] In some examples, the genotype of the patient to be treated is a T allele at polymorphism rs144829310 (SEQ ID NO: 50), a T allele at polymorphism rs72699186 (SEQ ID NO: 51), a G allele at polymorphism rs10975479 (SEQ ID NO: 52), a C allele at polymorphism rs72699191 (SEQ ID NO: 53), a G allele at polymorphism rs7032572 (SEQ ID NO: 54), a C allele at polymorphism rs1342326 (SEQ ID NO: 55). allele at polymorphism rs2066362 (SEQ ID NO: 56), T allele at polymorphism rs142807069 (SEQ ID NO: 57), G allele at polymorphism rs10975488 (SEQ ID NO: 58), and A allele at polymorphism rs9775039 (SEQ ID NO: 59).

[0079] In some examples, the genotype of the patient to be treated has been determined to include at least one allele of each of the following polymorphisms: a T allele at polymorphism rs144829310 (SEQ ID NO: 50), a T allele at polymorphism rs72699186 (SEQ ID NO: 51), a G allele at polymorphism rs10975479 (SEQ ID NO: 52), a C allele at polymorphism rs72699191 (SEQ ID NO: 53), a G allele at polymorphism rs7032572 (SEQ ID NO: 54), a C allele at polymorphism rs1342326 (SEQ ID NO: 55), a T allele at polymorphism rs2066362 (SEQ ID NO: 56), a G allele at polymorphism rs142807069 (SEQ ID NO: 57), and a G allele at polymorphism rs10975488 (SEQ ID NO: 58), and an A allele at polymorphism rs9775039 (SEQ ID NO: 59).

[0080] In some examples, the genotype of the patient to be treated is at least one of the following: a T allele at polymorphism rs144829310 (SEQ ID NO: 50) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; a T allele at polymorphism rs72699186 (SEQ ID NO: 51) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; a G allele at polymorphism rs10975479 (SEQ ID NO: 52) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; a C allele at polymorphism rs72699191 (SEQ ID NO: 53) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; a G allele at polymorphism rs7032572 (SEQ ID NO: 54) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; a C allele at polymorphism rs10975479 (SEQ ID NO: 55); It has been determined that the mutant contains at least one allele of a polymorphism selected from the C allele at polymorphism rs342326 (SEQ ID NO: 55) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the T allele at polymorphism rs2066362 (SEQ ID NO: 56) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the G allele at polymorphism rs142807069 (SEQ ID NO: 57) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the G allele at polymorphism rs10975488 (SEQ ID NO: 58) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, and the A allele at polymorphism rs9775039 (SEQ ID NO: 59) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith.

[0081] In some examples, the genotype of the patient to be treated has been determined to include at least one allele at a polymorphism selected from the T allele at polymorphism rs72699186 (SEQ ID NO: 51) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the G allele at polymorphism rs7032572 (SEQ ID NO: 54) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the T allele at polymorphism rs144829310 (SEQ ID NO: 50) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, and the G allele at polymorphism rs10975488 (SEQ ID NO: 58) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith.

[0082] In some examples, the genotype of the patient to be treated has been determined to include at least one allele at a polymorphism selected from the T allele at polymorphism rs72699186 (SEQ ID NO: 51), the G allele at polymorphism rs7032572 (SEQ ID NO: 54), the T allele at polymorphism rs144829310 (SEQ ID NO: 50), and the G allele at polymorphism rs10975488 (SEQ ID NO: 58).

[0083] In some examples, the genotype of the patient to be treated is determined to include two alleles at a polymorphism selected from two T alleles at polymorphism rs72699186 (SEQ ID NO: 51) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two G alleles at polymorphism rs7032572 (SEQ ID NO: 54) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two T alleles at polymorphism rs144829310 (SEQ ID NO: 50) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, and two G alleles at polymorphism rs10975488 (SEQ ID NO: 58) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith.

[0084] In some examples, the genotype of the patient to be treated is determined to include two alleles at a polymorphism selected from two T alleles at polymorphism rs72699186 (SEQ ID NO: 51), two G alleles at polymorphism rs7032572 (SEQ ID NO: 54), two T alleles at polymorphism rs144829310 (SEQ ID NO: 50), and two G alleles at polymorphism rs10975488 (SEQ ID NO: 58).

[0085] In some examples, the genotype of the patient to be treated has been determined to include at least one allele at a polymorphism selected from the G allele at polymorphism rs7032572 (SEQ ID NO: 54) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the T allele at polymorphism rs144829310 (SEQ ID NO: 50) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, and the G allele at polymorphism rs10975488 (SEQ ID NO: 58) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith.

[0086] In some examples, the genotype of the patient to be treated has been determined to include at least one allele at a polymorphism selected from the G allele at polymorphism rs7032572 (SEQ ID NO: 54), the T allele at polymorphism rs144829310 (SEQ ID NO: 50), and the G allele at polymorphism rs10975488 (SEQ ID NO: 58).

[0087] In some examples, the genotype of the patient to be treated has been determined to include two alleles at a polymorphism selected from two G alleles at polymorphism rs7032572 (SEQ ID NO: 54) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two T alleles at polymorphism rs144829310 (SEQ ID NO: 50) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, and two G alleles at polymorphism rs10975488 (SEQ ID NO: 58) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith.

[0088] In some examples, the genotype of a treated patient is determined to include two alleles at a polymorphism selected from two G alleles at polymorphism rs7032572 (SEQ ID NO: 54), two T alleles at polymorphism rs144829310 (SEQ ID NO: 50), and two G alleles at polymorphism rs10975488 (SEQ ID NO: 58). The examples show that each of these three alleles at these polymorphisms surprisingly increases expression from the IL-33 promoter under low and high cytokine conditions.

[0089] Polymorphisms in high linkage disequilibrium with two additional Cluster 3 polymorphisms or at least one Cluster 3 polymorphism listed in Table 2 include:

[0090] [Table 4]

[0091] The Examples show that these polymorphisms increase expression from the IL-33 promoter under basal, low cytokine, and / or high cytokine conditions, suggesting that these SNPs are causative in the pathogenesis of IL-33-mediated disorders.

[0092] In some examples, the genotype of the patient to be treated has been determined to include at least one T allele at polymorphism rs552376976 (SEQ ID NO: 87). In some examples, the genotype of the patient to be treated has been determined to include two T alleles at polymorphism rs552376976 (SEQ ID NO: 87). The examples show that the T allele at polymorphism rs552376976 enhances expression from the IL-33 promoter under low and high cytokine conditions.

[0093] In some examples, the genotype of the patient to be treated has been determined to include at least one T allele at the polymorphism rs13298116 (SEQ ID NO: 88). In some examples, the genotype of the patient to be treated has been determined to include two T alleles at the polymorphism rs13298116 (SEQ ID NO: 88). The examples show that the T allele at the polymorphism rs13298116 enhances expression from the IL-33 promoter under basal and high cytokine conditions.

[0094] In another aspect, methods are provided for treating a subject suffering from an IL-33-mediated disorder, comprising administering to the subject an IL-33 axis-binding antagonist, wherein the patient's genotype has been determined to include at least one allele of a Cluster 1 polymorphism as defined in Table 3, or an equivalent allele at a polymorphism in linkage disequilibrium therewith. In some examples, the patient's genotype includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of the Cluster 1 alleles listed in Table 3.

[0095] [Table 5]

[0096] The "Cluster 1" polymorphism defines an allelic polymorphism in the IL-33 genomic region at positions 6222149-6243392 on chromosome 9. As described in the Examples, the Cluster 1 polymorphism is associated with an increased risk (odds ratio (OR)) of asthma. The strongest association was observed for variant rs10975507 (OR=1.1 (CI 1.09-1.12), P=1.54×10-40 (see Table 7). The OR given is for individuals homozygous for the non-risk allele compared with those heterozygous. Interestingly, each of the cluster 1 polymorphisms is associated with an increased risk of early-onset disease. The association of rs10975507 with early-onset disease was OR=1.11 (CI 1.08-1.14), P=3.19×10-11. Surprisingly, the association with early-onset disease was independent of blood eosinophil counts (Table 8), suggesting that IL33-induced early-onset asthma is not solely mediated by high eosinophil counts.

[0097] Like the Cluster 2 and 3 polymorphisms, the Cluster 1 polymorphisms do not encode amino acid changes in the protein-coding region of the IL-33 gene, and therefore may cause IL-33-mediated pathologies through the regulatory mechanisms described above.

[0098] In some examples, the genotype of the patient to be treated is selected from the group consisting of a T allele at polymorphism rs10975507 (SEQ ID NO: 60) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a G allele at polymorphism rs10975504 (SEQ ID NO: 61) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a C allele at polymorphism rs10815393 (SEQ ID NO: 62) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a T allele at polymorphism rs12339348 (SEQ ID NO: 63 ... C allele at polymorphism rs12339348 (SEQ ID NO: 63) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a C allele at polymorphism rs12339348 (SEQ ID NO: 63) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a C allele at polymorphism rs12339348 (SEQ ID NO: 63) or at at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; the G allele at polymorphism rs7035413 (SEQ ID NO: 64) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; the C allele at polymorphism rs17498196 (SEQ ID NO: 65) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; the C allele at polymorphism rs17582919 (SEQ ID NO: 66) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; the G allele at polymorphism rs10815391 (SEQ ID NO: 67) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; the C allele at polymorphism rs10815392 (SEQ ID NO: 68) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; the C allele at polymorphism rs72689561 (SEQ ID NO: 69) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; the C allele at polymorphism rs7038893 (SEQ ID NO: 70) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; the T allele at polymorphism rs112935616 (SEQ ID NO: 71) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; It has been determined that the mutation contains at least one allele in a polymorphism selected from at least one equivalent allele in a polymorphism in equilibrium, the T allele in polymorphism rs10815376 (SEQ ID NO: 72) or at least one equivalent allele in a polymorphism in linkage disequilibrium therewith, the A allele in polymorphism rs12551268 (SEQ ID NO: 73) or at least one equivalent allele in a polymorphism in linkage disequilibrium therewith, and the G allele in polymorphism rs2006682 (SEQ ID NO: 74) or at least one equivalent allele in a polymorphism in linkage disequilibrium therewith.

[0099] In some examples, the genotype of the patient to be treated is a T allele at polymorphism rs10975507 (SEQ ID NO: 60), a G allele at polymorphism rs10975504 (SEQ ID NO: 61), a C allele at polymorphism rs10815393 (SEQ ID NO: 62), a T allele at polymorphism rs12339348 (SEQ ID NO: 63), a G allele at polymorphism rs7035413 (SEQ ID NO: 64), a C allele at polymorphism rs17498196 (SEQ ID NO: 65), a C allele at polymorphism rs17582919 (SEQ ID NO: 66), a C allele at polymorphism rs10815391 (SEQ ID NO: 67). It has been determined that the gene contains at least one allele of a polymorphism selected from the group consisting of the G allele at polymorphism rs10815392 (SEQ ID NO: 68), the C allele at polymorphism rs72689561 (SEQ ID NO: 69), the C allele at polymorphism rs7038893 (SEQ ID NO: 70), the T allele at polymorphism rs112935616 (SEQ ID NO: 71), the T allele at polymorphism rs10815376 (SEQ ID NO: 72), the A allele at polymorphism rs12551268 (SEQ ID NO: 73), and the G allele at polymorphism rs2006682 (SEQ ID NO: 74).

[0100] In some examples, the genotype of the patient to be treated is the T allele at polymorphism rs10975507 (SEQ ID NO: 60), the G allele at polymorphism rs10975504 (SEQ ID NO: 61), the C allele at polymorphism rs10815393 (SEQ ID NO: 62), the T allele at polymorphism rs12339348 (SEQ ID NO: 63), the G allele at polymorphism rs7035413 (SEQ ID NO: 64), the C allele at polymorphism rs17498196 (SEQ ID NO: 65), the C allele at polymorphism rs17582919 (SEQ ID NO: 66), the C allele at polymorphism rs10815391 ( It has been determined that the gene contains at least one allele of each of the following: the G allele at polymorphism rs10815392 (SEQ ID NO: 67), the C allele at polymorphism rs72689561 (SEQ ID NO: 69), the C allele at polymorphism rs7038893 (SEQ ID NO: 70), the T allele at polymorphism rs112935616 (SEQ ID NO: 71), the T allele at polymorphism rs10815376 (SEQ ID NO: 72), the A allele at polymorphism rs12551268 (SEQ ID NO: 73), and the G allele at polymorphism rs2006682 (SEQ ID NO: 74).

[0101] In some examples, the genotype of the patient to be treated is at least one of the following: a T allele at polymorphism rs10975507 (SEQ ID NO: 60) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; a G allele at polymorphism rs10975504 (SEQ ID NO: 61) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; a C allele at polymorphism rs10815393 (SEQ ID NO: 62) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; a T allele at polymorphism rs12339348 (SEQ ID NO: 63) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; a G allele at polymorphism rs7035413 (SEQ ID NO: 64) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; a C allele at polymorphism rs17498196 (SEQ ID NO: 65) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; the C allele at polymorphism rs10815392 (SEQ ID NO: 68) or at least one equivalent allele at polymorphism in linkage disequilibrium therewith; the C allele at polymorphism rs72689561 (SEQ ID NO: 69) or at least one equivalent allele at polymorphism in linkage disequilibrium therewith; the C allele at polymorphism rs7038893 (SEQ ID NO: 70) or at least one equivalent allele at polymorphism in linkage disequilibrium therewith; and the T allele at polymorphism rs112935616 (SEQ ID NO: 71) or at least one equivalent allele at polymorphism in linkage disequilibrium therewith.

[0102] In some examples, the genotype of the patient to be treated is a T allele at polymorphism rs10975507 (SEQ ID NO: 60), a G allele at polymorphism rs10975504 (SEQ ID NO: 61), a C allele at polymorphism rs10815393 (SEQ ID NO: 62), a T allele at polymorphism rs12339348 (SEQ ID NO: 63), a G allele at polymorphism rs7035413 (SEQ ID NO: 64), a C allele at polymorphism rs17498196 (SEQ ID NO: 65), a C allele at polymorphism rs175 It has been determined that the polymorphism contains at least one allele selected from the C allele at polymorphism rs82919 (SEQ ID NO: 66), the G allele at polymorphism rs10815391 (SEQ ID NO: 67), the C allele at polymorphism rs10815392 (SEQ ID NO: 68), the C allele at polymorphism rs72689561 (SEQ ID NO: 69), the C allele at polymorphism rs7038893 (SEQ ID NO: 70), and the T allele at polymorphism rs112935616 (SEQ ID NO: 71).

[0103] In some examples, the genotype of the patient to be treated is one of two T alleles at polymorphism rs10975507 (SEQ ID NO: 60) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two G alleles at polymorphism rs10975504 (SEQ ID NO: 61) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two C alleles at polymorphism rs10815393 (SEQ ID NO: 62) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two T alleles at polymorphism rs12339348 (SEQ ID NO: 63) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two G alleles at polymorphism rs7035413 (SEQ ID NO: 64) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two C alleles at polymorphism rs17498196 (SEQ ID NO: 65 ... C alleles at polymorphism rs17498196 (SEQ ID NO: 66) or two equivalent alleles at two C alleles at polymorphism rs17582919 (SEQ ID NO: 66) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith; two G alleles at polymorphism rs10815391 (SEQ ID NO: 67) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith; two C alleles at polymorphism rs10815392 (SEQ ID NO: 68) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith; two C alleles at polymorphism rs72689561 (SEQ ID NO: 69) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith; two C alleles at polymorphism rs7038893 (SEQ ID NO: 70) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith; and two T alleles at polymorphism rs112935616 (SEQ ID NO: 71) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith.

[0104] In some examples, the genotype of the patient to be treated is two T alleles at polymorphism rs10975507 (SEQ ID NO: 60), two G alleles at polymorphism rs10975504 (SEQ ID NO: 61), two C alleles at polymorphism rs10815393 (SEQ ID NO: 62), two T alleles at polymorphism rs12339348 (SEQ ID NO: 63), two G alleles at polymorphism rs7035413 (SEQ ID NO: 64), two C alleles at polymorphism rs17498196 (SEQ ID NO: 65 ... It has been determined to contain two alleles in polymorphisms selected from two C alleles in 17582919 (sequence number 66), two G alleles in polymorphism rs10815391 (sequence number 67), two C alleles in polymorphism rs10815392 (sequence number 68), two C alleles in polymorphism rs72689561 (sequence number 69), two C alleles in polymorphism rs7038893 (sequence number 70), and two T alleles in polymorphism rs112935616 (sequence number 71).

[0105] In some examples, the patient's genotype comprises at least one T allele at polymorphism rs10975507 (SEQ ID NO: 60) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith.

[0106] In some examples, the patient's genotype includes at least one T allele at polymorphism rs10975507 (SEQ ID NO: 60).

[0107] In some instances, the patient's genotype comprises two T alleles at polymorphism rs10975507 (SEQ ID NO: 60) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith.

[0108] In some examples, the patient's genotype includes two T alleles at polymorphism rs10975507 (SEQ ID NO: 60).

[0109] In some examples, the patient's genotype comprises at least one C allele at polymorphism rs7038893 (SEQ ID NO: 70) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith.

[0110] In some examples, the patient's genotype includes at least one C allele at polymorphism rs7038893 (SEQ ID NO: 70).

[0111] In some instances, the patient's genotype comprises two C alleles at polymorphism rs7038893 (SEQ ID NO: 70) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith.

[0112] In some examples, the patient's genotype includes two C alleles at polymorphism rs7038893 (SEQ ID NO: 70).

[0113] In another example, the Examples also disclose a series of SNPs that reduce the associated risk of having or developing an IL33-mediated disorder. The Examples show that having at least one allele of the polymorphisms shown in Table 4 reduces the odds ratio associated with the risk of having or developing the IL33-mediated disorder asthma.

[0114] [Table 6]

[0115] Thus, in any of the above methods, the patient's genotype may further be determined to be free of at least one polymorphism selected from the C allele at polymorphism rs370820588 (SEQ ID NO: 75), the C allele at polymorphism rs143215670 (SEQ ID NO: 76), the A allele at polymorphism rs343478 (SEQ ID NO: 77), the C allele at polymorphism rs146597587 (SEQ ID NO: 79), and the T allele at polymorphism rs10975519 (SEQ ID NO: 80).

[0116] In one example, the patient's genotype may be further determined to be free of at least one of each of the following polymorphisms: the C allele at polymorphism rs370820588 (SEQ ID NO: 75), the C allele at polymorphism rs143215670 (SEQ ID NO: 76), the A allele at polymorphism rs343478 (SEQ ID NO: 77), the C allele at polymorphism rs146597587 (SEQ ID NO: 79), and the T allele at polymorphism rs10975519 (SEQ ID NO: 80).

[0117] In one example, the patient's genotype may be further determined to not include two polymorphisms selected from two C alleles at polymorphism rs370820588 (SEQ ID NO: 75), two C alleles at polymorphism rs143215670 (SEQ ID NO: 76), two A alleles at polymorphism rs343478 (SEQ ID NO: 77), two C alleles at polymorphism rs146597587 (SEQ ID NO: 79), and two T alleles at polymorphism rs10975519 (SEQ ID NO: 80).

[0118] In one example, the patient's genotype may be further determined to be free of the following polymorphisms: two C alleles at polymorphism rs370820588 (SEQ ID NO: 75), two C alleles at polymorphism rs143215670 (SEQ ID NO: 76), two A alleles at polymorphism rs343478 (SEQ ID NO: 77), two C alleles at polymorphism rs146597587 (SEQ ID NO: 79), and two T alleles at polymorphism rs10975519 (SEQ ID NO: 80).

[0119] In particular examples, the patient's genotype has been determined to comprise a combination of the Cluster 1, 2, and 3 polymorphisms described above. In the examples above in which the patient's genotype has been determined to comprise a Cluster 2 polymorphism, the patient's genotype may be further determined to comprise at least one allele of a Cluster 3 polymorphism as defined in Table 2 and / or at least one allele of a Cluster 1 polymorphism as defined in Table 3. In examples in which the patient's genotype has been determined to comprise a Cluster 3 polymorphism, the patient's genotype may be further determined to comprise at least one allele of a Cluster 2 polymorphism as defined in Table 1 and / or at least one allele of a Cluster 1 polymorphism as defined in Table 3. In examples in which the patient's genotype has been determined to comprise a Cluster 1 polymorphism, the patient's genotype may be further determined to comprise at least one allele of a Cluster 2 polymorphism as defined in Table 1 and / or at least one allele of a Cluster 3 polymorphism as defined in Table 2.

[0120] Diagnostic methods The present disclosure also provides methods for determining or identifying whether a patient suffering from an IL-33-mediated disorder is likely to respond to a treatment comprising an IL-33 axis binding antagonist.

[0121] In some examples, the method comprises: (a) determining in a sample from the patient the genotype of at least one Cluster 2 polymorphism as defined in Table 1 or an equivalent allele at a polymorphism in linkage disequilibrium therewith; and (b) identifying the patient as likely to respond to a treatment comprising an IL-33 axis binding antagonist based on the genotype, wherein the presence of at least one allele of a Cluster 2 polymorphism or an equivalent allele at a polymorphism in linkage disequilibrium therewith indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0122] Cluster 2 In some examples, the polymorphism is selected from the group consisting of the G allele at polymorphism rs928413 (SEQ ID NO: 43) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the T allele at polymorphism rs1888909 (SEQ ID NO: 44) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the A allele at polymorphism rs992969 (SEQ ID NO: 45) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the T allele at polymorphism rs3939286 (SEQ ID NO: 46) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the A allele at polymorphism rs2381416 (SEQ ID NO: 47) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the T allele at polymorphism rs3939286 (SEQ ID NO: 48) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the A allele at polymorphism rs2381416 (SEQ ID NO: 49) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the T allele at polymorphism rs3939286 (SEQ ID NO: 50) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the T allele at polymorphism rs2381416 (SEQ ID NO: 51) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the A allele at polymorphism rs3939286 (SEQ ID NO: 52) or at least one equivalent allele at a polymorphism in linkage disequilibrium there The presence of at least one allele (e.g., 1, 2, 3, 4, 5, 6, or 7) selected from the C allele at polymorphism rs928412 (SEQ ID NO: 47) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the A allele at polymorphism rs928412 (SEQ ID NO: 48) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, and the T allele at polymorphism rs7848215 (SEQ ID NO: 49) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0123] In some examples, the presence of at least one allele at a polymorphism selected from a G allele at polymorphism rs928413 (SEQ ID NO: 43), a T allele at polymorphism rs1888909 (SEQ ID NO: 44), an A allele at polymorphism rs992969 (SEQ ID NO: 45), a T allele at polymorphism rs3939286 (SEQ ID NO: 46), a C allele at polymorphism rs2381416 (SEQ ID NO: 47), or an A allele at polymorphism rs928412 (SEQ ID NO: 48) indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0124] In some examples, the presence of at least one of each of the following polymorphisms: a G allele at polymorphism rs928413 (SEQ ID NO: 43), a T allele at polymorphism rs1888909 (SEQ ID NO: 44), an A allele at polymorphism rs992969 (SEQ ID NO: 45), a T allele at polymorphism rs3939286 (SEQ ID NO: 46), a C allele at polymorphism rs2381416 (SEQ ID NO: 47), an A allele at polymorphism rs928412 (SEQ ID NO: 48), a T allele at polymorphism rs7848215 (SEQ ID NO: 49) indicates that a patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0125] In some examples, two G alleles at polymorphism rs928413 (SEQ ID NO: 43) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two T alleles at polymorphism rs1888909 (SEQ ID NO: 44) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two A alleles at polymorphism rs992969 (SEQ ID NO: 45) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two T alleles at polymorphism rs3939286 (SEQ ID NO: 46) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two A alleles at polymorphism rs3939286 (SEQ ID NO: 47) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two A alleles at polymorphism rs3939286 (SEQ ID NO: 48) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two A alleles at polymorphism rs3939286 (SEQ ID NO: 49) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two A alleles at polymorphism rs3939286 (SEQ ID NO: 50) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two A alleles at polymorphism rs3939286 (SEQ ID NO: 51) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two A alleles at polymorphism rs3939286 (SEQ ID NO: 52) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two A alleles at polymorphism The presence of two alleles at a polymorphism selected from two C alleles at polymorphism rs2381416 (SEQ ID NO: 47) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two A alleles at polymorphism rs928412 (SEQ ID NO: 48) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, and two T alleles at polymorphism rs7848215 (SEQ ID NO: 49) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0126] In some examples, the presence of two alleles at a polymorphism selected from two alleles of a Cluster 2 polymorphism selected from two G alleles at polymorphism rs928413 (SEQ ID NO: 43), two T alleles at polymorphism rs1888909 (SEQ ID NO: 44), two A alleles at polymorphism rs992969 (SEQ ID NO: 45), two T alleles at polymorphism rs3939286 (SEQ ID NO: 46), two C alleles at polymorphism rs2381416 (SEQ ID NO: 47), two A alleles at polymorphism rs928412 (SEQ ID NO: 48), and two T alleles at polymorphism rs7848215 (SEQ ID NO: 49) indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0127] In some instances, the presence of at least one G allele at polymorphism rs928413 (SEQ ID NO: 43) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0128] In some instances, the presence of two G alleles at polymorphism rs928413 (SEQ ID NO: 43) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith indicates that a patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0129] In some examples, the presence of at least one G allele in polymorphism rs928413 (SEQ ID NO: 43) indicates that a patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0130] In some examples, the presence of two G alleles at polymorphism rs928413 (SEQ ID NO: 43) indicates that a patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0131] In some examples, the presence of at least one A allele at polymorphism rs992969 (SEQ ID NO: 45) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0132] In some examples, the presence of at least one A allele at polymorphism rs992969 (SEQ ID NO: 45) indicates that a patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0133] In some instances, the presence of two A alleles at polymorphism rs992969 (SEQ ID NO: 45) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith indicates that a patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0134] In some examples, the presence of two A alleles at polymorphism rs992969 (SEQ ID NO: 45) indicates that a patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0135] In some examples, the presence of at least one allele at a polymorphism selected from a C allele at polymorphism rs7046661 (SEQ ID NO: 82), a T allele at polymorphism rs10815363 (SEQ ID NO: 83), a T allele at polymorphism rs62558407 (SEQ ID NO: 84), a T allele at polymorphism rs1475658 (SEQ ID NO: 85), and a G allele at polymorphism rs10975481 (SEQ ID NO: 86) indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0136] In some examples, the presence of two alleles at a polymorphism selected from two C alleles at polymorphism rs7046661 (SEQ ID NO: 82), two T alleles at polymorphism rs10815363 (SEQ ID NO: 83), two T alleles at polymorphism rs62558407 (SEQ ID NO: 84), two T alleles at polymorphism rs1475658 (SEQ ID NO: 85), and two G alleles at polymorphism rs10975481 (SEQ ID NO: 86) indicates that a patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0137] In some instances, the presence of one or two T alleles at polymorphism rs10815363 (SEQ ID NO: 83) indicates that a patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0138] In some instances, the presence of one or two T alleles at polymorphism rs1475658 (SEQ ID NO: 85) indicates that a patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0139] Cluster 3 In some examples, the method comprises: (a) determining in a sample from the patient the genotype of at least one Cluster 3 polymorphism as defined in Table 2, or an equivalent allele at a polymorphism in linkage disequilibrium therewith; and (b) identifying the patient as likely to respond to a treatment comprising an IL-33 axis binding antagonist based on the genotype, wherein the presence of at least one allele of a Cluster 3 polymorphism, or an equivalent allele at a polymorphism in linkage disequilibrium therewith, indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0140] In some examples, the T allele at polymorphism rs144829310 (SEQ ID NO: 50), the T allele at polymorphism rs72699186 (SEQ ID NO: 51), the G allele at polymorphism rs10975479 (SEQ ID NO: 52), the C allele at polymorphism rs72699191 (SEQ ID NO: 53), the G allele at polymorphism rs7032572 (SEQ ID NO: 54), the C allele at polymorphism rs1342326 (SEQ ID NO: 55), the C allele at polymorphism rs2066362 (SEQ ID NO: 56), The presence of at least one allele (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) at a polymorphism selected from the T allele, the G allele at polymorphism rs142807069 (SEQ ID NO: 57) and the G allele at polymorphism rs10975488 (SEQ ID NO: 58), and the A allele at polymorphism rs9775039 (SEQ ID NO: 59) indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0141] In some examples, the following polymorphisms are present: a T allele at polymorphism rs144829310 (SEQ ID NO: 50), a T allele at polymorphism rs72699186 (SEQ ID NO: 51), a G allele at polymorphism rs10975479 (SEQ ID NO: 52), a C allele at polymorphism rs72699191 (SEQ ID NO: 53), a G allele at polymorphism rs7032572 (SEQ ID NO: 54), a G allele at polymorphism rs1342326 (SEQ ID NO: 55), The presence of at least one of each of the C allele, the T allele at polymorphism rs2066362 (SEQ ID NO: 56), the G allele at polymorphism rs142807069 (SEQ ID NO: 57), the G allele at polymorphism rs10975488 (SEQ ID NO: 58), and the A allele at polymorphism rs9775039 (SEQ ID NO: 59) indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0142] In some examples, the T allele at polymorphism rs144829310 (SEQ ID NO: 50) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the T allele at polymorphism rs72699186 (SEQ ID NO: 51) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the G allele at polymorphism rs10975479 (SEQ ID NO: 52) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the C allele at polymorphism rs72699191 (SEQ ID NO: 53) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the G allele at polymorphism rs7032572 (SEQ ID NO: 54) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the C allele at polymorphism rs1342326 (SEQ ID NO: 55) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, The presence of at least one allele at a polymorphism selected from at least one equivalent allele at a polymorphism in linkage disequilibrium, the T allele at polymorphism rs2066362 (SEQ ID NO: 56) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the G allele at polymorphism rs142807069 (SEQ ID NO: 57) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the G allele at polymorphism rs10975488 (SEQ ID NO: 58) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, and the A allele at polymorphism rs9775039 (SEQ ID NO: 59) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0143] In some examples, the presence of at least one allele at a polymorphism selected from the T allele at polymorphism rs72699186 (SEQ ID NO: 51) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith and the G allele at polymorphism rs7032572 (SEQ ID NO: 54) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0144] In some examples, the presence of at least one allele at a polymorphism selected from a T allele at polymorphism rs72699186 (SEQ ID NO: 51), a G allele at polymorphism rs7032572 (SEQ ID NO: 54), a T allele at polymorphism rs144829310 (SEQ ID NO: 50), and a G allele at polymorphism rs10975488 (SEQ ID NO: 58) indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0145] In some examples, the presence of two alleles at a polymorphism selected from two T alleles at polymorphism rs72699186 (SEQ ID NO: 51) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two G alleles at polymorphism rs7032572 (SEQ ID NO: 54), two T alleles at polymorphism rs144829310 (SEQ ID NO: 50) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, and two G alleles at polymorphism rs10975488 (SEQ ID NO: 58) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0146] In some examples, the presence of two alleles at a polymorphism selected from two T alleles at polymorphism rs72699186 (SEQ ID NO: 51), two G alleles at polymorphism rs7032572 (SEQ ID NO: 54), two T alleles at polymorphism rs144829310 (SEQ ID NO: 50), and two G alleles at polymorphism rs10975488 (SEQ ID NO: 58) indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0147] In some examples, the presence of at least one allele at a polymorphism selected from a G allele at polymorphism rs7032572 (SEQ ID NO: 54), a T allele at polymorphism rs144829310 (SEQ ID NO: 50), and a G allele at polymorphism rs10975488 (SEQ ID NO: 58) indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0148] In some examples, the presence of two alleles at a polymorphism selected from two G alleles at polymorphism rs7032572 (SEQ ID NO: 54), two T alleles at polymorphism rs144829310 (SEQ ID NO: 50), and two G alleles at polymorphism rs10975488 (SEQ ID NO: 58) indicates that a patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0149] In some instances, the presence of one or two T alleles at polymorphism rs552376976 (SEQ ID NO: 87) indicates that a patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0150] In some examples, the presence of one or two T alleles at polymorphism rs13298116 (SEQ ID NO: 88) indicates that a patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0151] Cluster 1 In some examples, the method comprises: (a) determining in a sample from the patient the genotype of at least one Cluster 1 polymorphism as defined in Table 3, or an equivalent allele at a polymorphism in linkage disequilibrium therewith; and (b) identifying the patient as likely to respond to a treatment comprising an IL-33 axis binding antagonist based on the genotype, wherein the presence of at least one allele of the Cluster 1 polymorphism, or an equivalent allele at a polymorphism in linkage disequilibrium therewith, indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0152] In some examples, the T allele at polymorphism rs10975507 (SEQ ID NO: 60) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the G allele at polymorphism rs10975504 (SEQ ID NO: 61) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the C allele at polymorphism rs10815393 (SEQ ID NO: 62) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the T allele at polymorphism rs12339348 (SEQ ID NO: 63) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a covalent allele, a G allele in polymorphism rs7035413 (SEQ ID NO: 64) or at least one equivalent allele in a polymorphism in linkage disequilibrium therewith, a C allele in polymorphism rs17498196 (SEQ ID NO: 65) or at least one equivalent allele in a polymorphism in linkage disequilibrium therewith, a C allele in polymorphism rs17582919 (SEQ ID NO: 66) or at least one equivalent allele in a polymorphism in linkage disequilibrium therewith, a G allele in polymorphism rs10815391 (SEQ ID NO: 67) or at least one equivalent allele in a polymorphism in linkage disequilibrium therewith, a polymorphism the C allele in polymorphism rs10815392 (SEQ ID NO: 68) or at least one equivalent allele in a polymorphism in linkage disequilibrium therewith; the C allele in polymorphism rs72689561 (SEQ ID NO: 69) or at least one equivalent allele in a polymorphism in linkage disequilibrium therewith; the C allele in polymorphism rs7038893 (SEQ ID NO: 70) or at least one equivalent allele in a polymorphism in linkage disequilibrium therewith; the T allele in polymorphism rs112935616 (SEQ ID NO: 71) or at least one equivalent allele in a polymorphism in linkage disequilibrium therewith; At least one allele (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 12The presence of 14 or 15 of these genes indicates that the patient has an increased likelihood of responding to therapy involving an IL-33 axis binding antagonist.

[0153] In some examples, the T allele at polymorphism rs10975507 (SEQ ID NO: 60), the G allele at polymorphism rs10975504 (SEQ ID NO: 61), the C allele at polymorphism rs10815393 (SEQ ID NO: 62), the T allele at polymorphism rs12339348 (SEQ ID NO: 63), the G allele at polymorphism rs7035413 (SEQ ID NO: 64), the C allele at polymorphism rs17498196 (SEQ ID NO: 65), the C allele at polymorphism rs17582919 (SEQ ID NO: 66), the G allele at polymorphism rs10815391 (SEQ ID NO: 67), the G allele at polymorphism rs10815392 (SEQ ID NO: 68), the G allele at polymorphism rs10815393 (SEQ ID NO: 69), the G allele at polymorphism rs10815394 (SEQ ID NO: 70), the G allele at polymorphism rs10815395 (SEQ ID NO: 71), the G allele at polymorphism rs10815396 (SEQ ID NO: 72), the G allele at polymorphism rs10815397 (SEQ ID NO: 73), the G allele at polymorphism rs10815398 (SEQ ID NO: 74), the G allele at polymorphism rs10815399 (SEQ ID NO: 75), the G allele at polymorphism rs10815398 (SEQ ID NO: 76), the G allele at polymorphism rs10815399 (SEQ ID NO: 77), the G allele the presence of at least one allele at a polymorphism selected from: a C allele at polymorphism rs72689561 (SEQ ID NO: 69), a C allele at polymorphism rs7038893 (SEQ ID NO: 70), a T allele at polymorphism rs112935616 (SEQ ID NO: 71), a T allele at polymorphism rs10815376 (SEQ ID NO: 72), an A allele at polymorphism rs12551268 (SEQ ID NO: 73), or a G allele at polymorphism rs2006682 (SEQ ID NO: 74) indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0154] In some examples, the following polymorphisms are present: a T allele at polymorphism rs10975507 (SEQ ID NO: 60), a G allele at polymorphism rs10975504 (SEQ ID NO: 61), a C allele at polymorphism rs10815393 (SEQ ID NO: 62), a T allele at polymorphism rs12339348 (SEQ ID NO: 63), a G allele at polymorphism rs7035413 (SEQ ID NO: 64), a C allele at polymorphism rs17498196 (SEQ ID NO: 65), a C allele at polymorphism rs17582919 (SEQ ID NO: 66), a G allele at polymorphism rs10815391 (SEQ ID NO: 67), a G allele at polymorphism rs10815392 (SEQ ID NO: 68), a G allele at polymorphism rs10815393 (SEQ ID NO: 69), a G allele at polymorphism rs10815394 (SEQ ID NO: 70), a G allele at polymorphism rs10815395 (SEQ ID NO: 71), a G allele at polymorphism rs10815396 (SEQ ID NO: 72), a G allele at polymorphism rs10815397 (SEQ ID NO: 73), a G allele at polymorphism rs10815398 (SEQ ID NO: 74), a G allele at polymorphism rs10815399 (SEQ ID NO: 75), a G allele at polymorphism rs10815399 (SEQ ID NO: 76), a G allele at polymorphism rs10815399 (SEQ ID NO The presence of at least one of each of the C allele at polymorphism rs5392 (SEQ ID NO: 68), the C allele at polymorphism rs72689561 (SEQ ID NO: 69), the C allele at polymorphism rs7038893 (SEQ ID NO: 70), the T allele at polymorphism rs112935616 (SEQ ID NO: 71), the T allele at polymorphism rs10815376 (SEQ ID NO: 72), the A allele at polymorphism rs12551268 (SEQ ID NO: 73), and the G allele at polymorphism rs2006682 (SEQ ID NO: 74) indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0155] In some examples, the polymorphism is selected from the group consisting of the T allele at polymorphism rs10975507 (SEQ ID NO: 60) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the G allele at polymorphism rs10975504 (SEQ ID NO: 61) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the C allele at polymorphism rs10815393 (SEQ ID NO: 62) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the C allele at polymorphism rs1233934 (SEQ ID NO: 63) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the C allele at polymorphism rs1233934 (SEQ ID NO: 64) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the C allele at polymorphism rs1233934 (SEQ ID NO: 65) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the C allele at polymorphism rs1233934 (SEQ ID NO: 66) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the C allele at polymorphism rs1233934 (SEQ ID NO: 67) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the C allele at polymorphism rs1233934 (SEQ ID NO: 68) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the C allele at polymorphism rs1233934 (SEQ ID NO: 69) or at least one equivalent allele at a polymorphism in linkage dis the T allele in polymorphism rs7035413 (SEQ ID NO: 64) or at least one equivalent allele in polymorphisms in linkage disequilibrium therewith; the G allele in polymorphism rs7035413 (SEQ ID NO: 64) or at least one equivalent allele in polymorphisms in linkage disequilibrium therewith; the C allele in polymorphism rs17498196 (SEQ ID NO: 65) or at least one equivalent allele in polymorphisms in linkage disequilibrium therewith; the C allele in polymorphism rs17582919 (SEQ ID NO: 66) or at least one equivalent allele in polymorphisms in linkage disequilibrium therewith; The presence of at least one allele at a polymorphism selected from at least one equivalent allele at a polymorphism in linkage disequilibrium, the G allele at polymorphism rs10815391 (SEQ ID NO: 67) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the C allele at polymorphism rs10815392 (SEQ ID NO: 68) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the C allele at polymorphism rs72689561 (SEQ ID NO: 69) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the C allele at polymorphism rs7038893 (SEQ ID NO: 70) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, or the T allele at polymorphism rs112935616 (SEQ ID NO: 71) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0156] In some examples, the T allele at polymorphism rs10975507 (SEQ ID NO: 60), the G allele at polymorphism rs10975504 (SEQ ID NO: 61), the C allele at polymorphism rs10815393 (SEQ ID NO: 62), the T allele at polymorphism rs12339348 (SEQ ID NO: 63), the G allele at polymorphism rs7035413 (SEQ ID NO: 64), the C allele at polymorphism rs17498196 (SEQ ID NO: 65), the C allele at polymorphism rs17582919 (SEQ ID NO: 66), the C allele at polymorphism rs The presence of at least one allele at a polymorphism selected from the G allele at 10815391 (SEQ ID NO: 67), the C allele at polymorphism rs10815392 (SEQ ID NO: 68), the C allele at polymorphism rs72689561 (SEQ ID NO: 69), the C allele at polymorphism rs7038893 (SEQ ID NO: 70), or the T allele at polymorphism rs112935616 (SEQ ID NO: 71) indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0157] In some examples, the polymorphisms include two T alleles at polymorphism rs10975507 (SEQ ID NO: 60) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith; two G alleles at polymorphism rs10975504 (SEQ ID NO: 61) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith; two C alleles at polymorphism rs10815393 (SEQ ID NO: 62) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith; and polymorphism rs123393 two T alleles in polymorphism rs7035413 (SEQ ID NO: 64) or two equivalent alleles in polymorphism in linkage disequilibrium therewith; two G alleles in polymorphism rs17498196 (SEQ ID NO: 65) or two equivalent alleles in polymorphism in linkage disequilibrium therewith; two C alleles in polymorphism rs17582919 (SEQ ID NO: 66) two G alleles at polymorphism rs10815391 (SEQ ID NO: 67) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith; two C alleles at polymorphism rs10815392 (SEQ ID NO: 68) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith; two C alleles at polymorphism rs72689561 (SEQ ID NO: 69) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith; two C alleles at polymorphism rs7038893 (SEQ ID NO: 70) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith; or two T alleles at polymorphism rs112935616 (SEQ ID NO: 71) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0158] In some examples, two T alleles at polymorphism rs10975507 (SEQ ID NO: 60), two G alleles at polymorphism rs10975504 (SEQ ID NO: 61), two C alleles at polymorphism rs10815393 (SEQ ID NO: 62), two T alleles at polymorphism rs12339348 (SEQ ID NO: 63), two G alleles at polymorphism rs7035413 (SEQ ID NO: 64), two C alleles at polymorphism rs17498196 (SEQ ID NO: 65), two C alleles at polymorphism rs17582919 (SEQ ID NO: 66), The presence of two alleles at a polymorphism selected from two G alleles at polymorphism rs10815391 (SEQ ID NO: 67), two C alleles at polymorphism rs10815392 (SEQ ID NO: 68), two C alleles at polymorphism rs72689561 (SEQ ID NO: 69), two C alleles at polymorphism rs7038893 (SEQ ID NO: 70), and two T alleles at polymorphism rs112935616 (SEQ ID NO: 71) indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0159] In some examples, the presence of at least one T allele at polymorphism rs10975507 (SEQ ID NO: 60) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0160] In some examples, the presence of at least one T allele at polymorphism rs10975507 (SEQ ID NO: 60) indicates that a patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0161] In some instances, the presence of two T alleles at polymorphism rs10975507 (SEQ ID NO: 60) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith indicates that a patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0162] In some examples, the presence of two T alleles at polymorphism rs10975507 (SEQ ID NO: 60) indicates that a patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0163] In some examples, the presence of one or two C alleles at polymorphism rs7038893 (SEQ ID NO: 70) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith indicates that a patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0164] In some instances, the presence of one or two C alleles at polymorphism rs7038893 (SEQ ID NO: 70) indicates that a patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0165] Cluster 4 In some examples, any of the diagnostic methods disclosed herein further comprise: (a) determining the genotype of at least one polymorphism defined in Table 4 in a sample from the patient; (b) identifying the patient as likely to respond to a treatment comprising an IL-33 axis binding antagonist based on the genotype, wherein the absence of at least one allele of a polymorphism defined in Table 4 indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0166] In some examples, the absence of at least one polymorphism selected from the C allele at polymorphism rs370820588 (SEQ ID NO: 75), the C allele at polymorphism rs143215670 (SEQ ID NO: 76), the A allele at polymorphism rs343478 (SEQ ID NO: 77), the C allele at polymorphism rs146597587 (SEQ ID NO: 79), and the T allele at polymorphism rs10975519 (SEQ ID NO: 80) indicates that the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0167] In one example, the patient's genotype has been determined to not include at least one of each of the following polymorphisms: the C allele at polymorphism rs370820588 (SEQ ID NO: 75), the C allele at polymorphism rs143215670 (SEQ ID NO: 76), the A allele at polymorphism rs343478 (SEQ ID NO: 77), the C allele at polymorphism rs146597587 (SEQ ID NO: 79), and the T allele at polymorphism rs10975519 (SEQ ID NO: 80), indicating the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0168] In one example, the patient's genotype is determined to not include two polymorphisms selected from two C alleles at polymorphism rs370820588 (SEQ ID NO: 75), two C alleles at polymorphism rs143215670 (SEQ ID NO: 76), two A alleles at polymorphism rs343478 (SEQ ID NO: 77), two C alleles at polymorphism rs146597587 (SEQ ID NO: 79), and two T alleles at polymorphism rs10975519 (SEQ ID NO: 80), indicating the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0169] In one example, the patient's genotype is determined to not include the following polymorphisms: two C alleles at polymorphism rs370820588 (SEQ ID NO: 75), two C alleles at polymorphism rs143215670 (SEQ ID NO: 76), two A alleles at polymorphism rs343478 (SEQ ID NO: 77), two C alleles at polymorphism rs146597587 (SEQ ID NO: 79), and two T alleles at polymorphism rs10975519 (SEQ ID NO: 80), indicating the patient has an increased likelihood of responding to a treatment comprising an IL-33 axis binding antagonist.

[0170] The present disclosure also provides methods for determining whether a patient is at increased risk for an IL-33-mediated disorder.

[0171] In some examples, the method for determining whether a patient is at increased risk for an IL-33 mediated disorder comprises identifying, from a sample obtained from the patient, a genotype for at least one Cluster 2 polymorphism as defined in Table 1 or an equivalent allele of a polymorphism in linkage disequilibrium therewith, wherein if the patient's genotype comprises at least one Cluster 2 polymorphism as defined in Table 1 or an equivalent allele of a polymorphism in linkage disequilibrium therewith, the patient is at increased risk for an IL-33 mediated disorder.

[0172] Cluster 2 In some examples, the patient's genotype is selected from the group consisting of a G allele at polymorphism rs928413 (SEQ ID NO: 43) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a T allele at polymorphism rs1888909 (SEQ ID NO: 44) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, an A allele at polymorphism rs992969 (SEQ ID NO: 45) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a T allele at polymorphism rs3939286 (SEQ ID NO: 46) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a T allele at polymorphism rs3939286 (SEQ ID NO: 47) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a T allele at polymorphism rs3939286 (SEQ ID NO: 48) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a T allele at polymorphism rs3939286 (SEQ ID NO: 49) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a T allele at polymorphism rs3939286 (SEQ ID NO: 50) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a T allele at polymorphism rs3939286 (SEQ ID NO: 51) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a T allele at polymorphism rs3939286 (SEQ ID NO: 52) or at least one equivalent allele at a polymorphism in linkage disequ the C allele at polymorphism rs2381416 (SEQ ID NO: 47) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; the A allele at polymorphism rs928412 (SEQ ID NO: 48) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; and the T allele at polymorphism rs7848215 (SEQ ID NO: 49) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith.

[0173] In some examples, the patient's genotype includes at least one allele (e.g., one, two, three, four, five, six, or seven) at a polymorphism selected from a G allele at polymorphism rs928413 (SEQ ID NO: 43), a T allele at polymorphism rs1888909 (SEQ ID NO: 44), an A allele at polymorphism rs992969 (SEQ ID NO: 45), a T allele at polymorphism rs3939286 (SEQ ID NO: 46), a C allele at polymorphism rs2381416 (SEQ ID NO: 47), an A allele at polymorphism rs928412 (SEQ ID NO: 48), and a T allele at polymorphism rs7848215 (SEQ ID NO: 49).

[0174] In some examples, the patient's genotype includes at least one of each of the following polymorphisms: a G allele at polymorphism rs928413 (SEQ ID NO: 43), a T allele at polymorphism rs1888909 (SEQ ID NO: 44), an A allele at polymorphism rs992969 (SEQ ID NO: 45), a T allele at polymorphism rs3939286 (SEQ ID NO: 46), a C allele at polymorphism rs2381416 (SEQ ID NO: 47), an A allele at polymorphism rs928412 (SEQ ID NO: 48), and a T allele at polymorphism rs7848215 (SEQ ID NO: 49).

[0175] In some examples, the patient's genotype comprises two alleles at polymorphisms selected from two G alleles at polymorphism rs928413 (SEQ ID NO: 43), two T alleles at polymorphism rs1888909 (SEQ ID NO: 44), two A alleles at polymorphism rs992969 (SEQ ID NO: 45), two T alleles at polymorphism rs3939286 (SEQ ID NO: 46), two C alleles at polymorphism rs2381416 (SEQ ID NO: 47), two A alleles at polymorphism rs928412 (SEQ ID NO: 48), and two T alleles at polymorphism rs7848215 (SEQ ID NO: 49).

[0176] In some examples, the patient's genotype is two G alleles at polymorphism rs928413 (SEQ ID NO: 43) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith; two T alleles at polymorphism rs1888909 (SEQ ID NO: 44) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith; two A alleles at polymorphism rs992969 (SEQ ID NO: 45) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith; two T alleles at polymorphism rs3939286 (SEQ ID NO: 46) or two equivalent alleles at polymorphism rs1888909 (SEQ ID NO: 47) includes two alleles at a polymorphism selected from two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two C alleles at polymorphism rs2381416 (SEQ ID NO: 47) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two A alleles at polymorphism rs928412 (SEQ ID NO: 48) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, and two T alleles at polymorphism rs7848215 (SEQ ID NO: 49) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith.

[0177] In some examples, the patient's genotype includes at least one G allele at polymorphism rs928413 (SEQ ID NO: 43) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith.

[0178] In some examples, the patient's genotype includes at least one G allele at polymorphism rs928413 (SEQ ID NO: 43).

[0179] In some instances, the patient's genotype includes two G alleles at polymorphism rs928413 (SEQ ID NO: 43) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith.

[0180] In some examples, the patient's genotype includes two G alleles at polymorphism rs928413 (SEQ ID NO: 43).

[0181] In some examples, the patient's genotype comprises at least one A allele at polymorphism rs992969 (SEQ ID NO: 45) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith.

[0182] In some examples, the patient's genotype includes at least one A allele at polymorphism rs992969 (SEQ ID NO: 45).

[0183] In some instances, the patient's genotype comprises two A alleles at polymorphism rs992969 (SEQ ID NO: 45) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith.

[0184] In some examples, the patient's genotype includes two A alleles at polymorphism rs992969 (SEQ ID NO: 45).

[0185] In some examples, the patient's genotype includes at least one allele selected from a C allele at polymorphism rs7046661 (SEQ ID NO: 82), a T allele at polymorphism rs10815363 (SEQ ID NO: 83), a T allele at polymorphism rs62558407 (SEQ ID NO: 84), a T allele at polymorphism rs1475658 (SEQ ID NO: 85), and a G allele at polymorphism rs10975481 (SEQ ID NO: 86).

[0186] In some examples, the patient's genotype comprises two alleles at polymorphisms selected from two C alleles at polymorphism rs7046661 (SEQ ID NO: 82), two T alleles at polymorphism rs10815363 (SEQ ID NO: 83), two T alleles at polymorphism rs62558407 (SEQ ID NO: 84), two T alleles at polymorphism rs1475658 (SEQ ID NO: 85), and two G alleles at polymorphism rs10975481 (SEQ ID NO: 86).

[0187] In some examples, the patient's genotype includes one or two T alleles at polymorphism rs10815363 (SEQ ID NO: 83).

[0188] In some examples, the patient's genotype includes one or two T alleles at polymorphism rs1475658 (SEQ ID NO: 85).

[0189] Cluster 3 In some examples, the method for determining whether a patient has an increased risk of an IL-33 mediated disorder comprises identifying, from a sample obtained from the patient, a genotype for at least one Cluster 3 polymorphism as defined in Table 2, or an equivalent allele of a polymorphism in linkage disequilibrium therewith; wherein if the patient's genotype comprises at least one Cluster 3 polymorphism as defined in Table 2, or an equivalent allele of a polymorphism in linkage disequilibrium therewith, the patient is at increased risk of an IL-33 mediated disorder.

[0190] In some examples, the patient's genotype comprises at least one allele at a polymorphism selected from a T allele at polymorphism rs144829310 (SEQ ID NO: 50), a T allele at polymorphism rs72699186 (SEQ ID NO: 51), a G allele at polymorphism rs10975479 (SEQ ID NO: 52), a C allele at polymorphism rs72699191 (SEQ ID NO: 53), a G allele at polymorphism rs7032572 (SEQ ID NO: 54), a C allele at polymorphism rs1342326 (SEQ ID NO: 55), a T allele at polymorphism rs2066362 (SEQ ID NO: 56), a G allele at polymorphism rs142807069 (SEQ ID NO: 57), a G allele at polymorphism rs10975488 (SEQ ID NO: 58), and an A allele at polymorphism rs9775039 (SEQ ID NO: 59).

[0191] In some examples, the patient's genotype includes at least one of each of the following polymorphisms: a T allele at polymorphism rs144829310 (SEQ ID NO: 50), a T allele at polymorphism rs72699186 (SEQ ID NO: 51), a G allele at polymorphism rs10975479 (SEQ ID NO: 52), a C allele at polymorphism rs72699191 (SEQ ID NO: 53), a G allele at polymorphism rs7032572 (SEQ ID NO: 54), a C allele at polymorphism rs1342326 (SEQ ID NO: 55), a T allele at polymorphism rs2066362 (SEQ ID NO: 56), a G allele at polymorphism rs142807069 (SEQ ID NO: 57), and a G allele at polymorphism rs10975488 (SEQ ID NO: 58), and an A allele at polymorphism rs9775039 (SEQ ID NO: 59).

[0192] In some examples, the patient's genotype is selected from the group consisting of a T allele at polymorphism rs144829310 (SEQ ID NO: 50) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a T allele at polymorphism rs72699186 (SEQ ID NO: 51) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a G allele at polymorphism rs10975479 (SEQ ID NO: 52) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a C allele at polymorphism rs72699191 (SEQ ID NO: 53) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a G allele at polymorphism rs7032572 (SEQ ID NO: 54) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a C allele at polymorphism rs7032572 (SEQ ID NO: 55) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a G allele at polymorphism rs10975479 (SEQ ID NO: 56) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a C allele at polymorphism rs7032572 (SEQ ID NO: 57) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a G allele at polymorphism rs10975479 (SEQ ID NO: 58) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a C allele at polymorphism rs10975479 (SEQ ID NO: 59) or at least one equivalent allele The polymorphisms include at least one allele of a polymorphism selected from the C allele at rs1342326 (SEQ ID NO: 55) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the T allele at rs2066362 (SEQ ID NO: 56) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the G allele at rs142807069 (SEQ ID NO: 57) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the G allele at rs10975488 (SEQ ID NO: 58) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, and the A allele at rs9775039 (SEQ ID NO: 59) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith.

[0193] In some examples, the patient's genotype comprises at least one allele at a polymorphism selected from the T allele at polymorphism rs72699186 (SEQ ID NO: 51) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the G allele at polymorphism rs7032572 (SEQ ID NO: 54) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the T allele at polymorphism rs144829310 (SEQ ID NO: 50) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, and the G allele at polymorphism rs10975488 (SEQ ID NO: 58) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith.

[0194] In some examples, the patient's genotype comprises at least one allele at a polymorphism selected from a T allele at polymorphism rs72699186 (SEQ ID NO: 51), a G allele at polymorphism rs7032572 (SEQ ID NO: 54), a T allele at polymorphism rs144829310 (SEQ ID NO: 50), and a G allele at polymorphism rs10975488 (SEQ ID NO: 58).

[0195] In some examples, the patient's genotype comprises two alleles at a polymorphism selected from two T alleles at polymorphism rs72699186 (SEQ ID NO: 51) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two G alleles at polymorphism rs7032572 (SEQ ID NO: 54) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two T alleles at polymorphism rs144829310 (SEQ ID NO: 50) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, and two G alleles at polymorphism rs10975488 (SEQ ID NO: 58) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith.

[0196] In some examples, the patient's genotype comprises two alleles at polymorphisms selected from two T alleles at polymorphism rs72699186 (SEQ ID NO: 51) and two G alleles at polymorphism rs7032572 (SEQ ID NO: 54), two T alleles at polymorphism rs144829310 (SEQ ID NO: 50), and two G alleles at polymorphism rs10975488 (SEQ ID NO: 58).

[0197] In some examples, the genotype comprises at least one allele at a polymorphism selected from the G allele at polymorphism rs7032572 (SEQ ID NO: 54) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the T allele at polymorphism rs144829310 (SEQ ID NO: 50) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, and the G allele at polymorphism rs10975488 (SEQ ID NO: 58) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith.

[0198] In some examples, the patient's genotype includes at least one allele at a polymorphism selected from the G allele at polymorphism rs7032572 (SEQ ID NO: 54), the T allele at polymorphism rs144829310 (SEQ ID NO: 50), and the G allele at polymorphism rs10975488 (SEQ ID NO: 58).

[0199] In some examples, the patient's genotype comprises two alleles at a polymorphism selected from two G alleles at polymorphism rs7032572 (SEQ ID NO: 54) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two T alleles at polymorphism rs144829310 (SEQ ID NO: 50) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, and two G alleles at polymorphism rs10975488 (SEQ ID NO: 58) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith.

[0200] In some examples, the patient's genotype comprises two alleles at a polymorphism selected from two G alleles at polymorphism rs7032572 (SEQ ID NO: 54), two T alleles at polymorphism rs144829310 (SEQ ID NO: 50), and two G alleles at polymorphism rs10975488 (SEQ ID NO: 58). The examples show that each of these three alleles at these polymorphisms surprisingly increases expression from the IL-33 promoter under low and high cytokine conditions.

[0201] In some examples, the patient's genotype includes one or two T alleles at polymorphism rs552376976 (SEQ ID NO: 87).

[0202] In some examples, the patient's genotype includes one or two T alleles at polymorphism rs13298116 (SEQ ID NO: 88).

[0203] Cluster 1 In some examples, the method for determining whether a patient has an increased risk of an IL-33 mediated disorder comprises identifying, from a sample obtained from the patient, a genotype for at least one Cluster 1 polymorphism as defined in Table 3, or an equivalent allele of a polymorphism in linkage disequilibrium therewith; wherein if the patient's genotype comprises at least one Cluster 1 polymorphism as defined in Table 3, or an equivalent allele of a polymorphism in linkage disequilibrium therewith, the patient is at increased risk of an IL-33 mediated disorder.

[0204] In some examples, the patient's genotype is selected from the group consisting of a T allele at polymorphism rs10975507 (SEQ ID NO: 60) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a G allele at polymorphism rs10975504 (SEQ ID NO: 61) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a C allele at polymorphism rs10815393 (SEQ ID NO: 62) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a T allele at polymorphism rs12339348 (SEQ ID NO: 63 ... C allele at polymorphism rs12339348 (SEQ ID NO: 63) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a C allele at polymorphism rs12339348 (SEQ ID NO: 63) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, a C allele at polymorphism rs12339348 (SEQ ID NO: 63) or at least one equivalent at least one equivalent allele, the G allele at polymorphism rs7035413 (SEQ ID NO: 64) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the C allele at polymorphism rs17498196 (SEQ ID NO: 65) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the C allele at polymorphism rs17582919 (SEQ ID NO: 66) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith, the G allele at polymorphism rs10815391 (SEQ ID NO: 67) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith a C allele in polymorphism rs10815392 (SEQ ID NO: 68) or at least one equivalent allele in a polymorphism in linkage disequilibrium therewith; a C allele in polymorphism rs72689561 (SEQ ID NO: 69) or at least one equivalent allele in a polymorphism in linkage disequilibrium therewith; a C allele in polymorphism rs7038893 (SEQ ID NO: 70) or at least one equivalent allele in a polymorphism in linkage disequilibrium therewith; a T allele in polymorphism rs112935616 (SEQ ID NO: 71) or at least one equivalent allele in a polymorphism in linkage disequilibrium therewith; At least one allele (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 1213, 14 or 15).

[0205] In some examples, the patient's genotype is a T allele at polymorphism rs10975507 (SEQ ID NO: 60), a G allele at polymorphism rs10975504 (SEQ ID NO: 61), a C allele at polymorphism rs10815393 (SEQ ID NO: 62), a T allele at polymorphism rs12339348 (SEQ ID NO: 63), a G allele at polymorphism rs7035413 (SEQ ID NO: 64), a C allele at polymorphism rs17498196 (SEQ ID NO: 65), a C allele at polymorphism rs17582919 (SEQ ID NO: 66), a C allele at polymorphism rs10815391 (SEQ ID NO: 67), a T allele at polymorphism rs12339348 (SEQ ID NO: 68), a G allele at polymorphism rs7035413 (SEQ ID NO: 69), a C allele at polymorphism rs17498196 (SEQ ID NO: 69), a C allele at polymorphism rs17582919 (SEQ ID NO: 70), a C allele at polymorphism rs10815391 (SEQ ID NO: 71), a C allele at polymorphism rs17498196 (SEQ ID NO: 72), a C allele at polymorphism rs17582919 (SEQ ID NO: 73), a C allele at polymorphism rs17498196 (SEQ ID NO: 74), a C allele at polymorphism rs17582919 (SEQ ID NO: 75), a C allele at polymorphism rs10815391 (SEQ ID NO: 7), the G allele at polymorphism rs10815392 (SEQ ID NO: 68), the C allele at polymorphism rs72689561 (SEQ ID NO: 69), the C allele at polymorphism rs7038893 (SEQ ID NO: 70), the T allele at polymorphism rs112935616 (SEQ ID NO: 71), the T allele at polymorphism rs10815376 (SEQ ID NO: 72), the A allele at polymorphism rs12551268 (SEQ ID NO: 73), and the G allele at polymorphism rs2006682 (SEQ ID NO: 74).

[0206] In some examples, the patient's genotype is the T allele at polymorphism rs10975507 (SEQ ID NO: 60), the G allele at polymorphism rs10975504 (SEQ ID NO: 61), the C allele at polymorphism rs10815393 (SEQ ID NO: 62), the T allele at polymorphism rs12339348 (SEQ ID NO: 63), the G allele at polymorphism rs7035413 (SEQ ID NO: 64), the C allele at polymorphism rs17498196 (SEQ ID NO: 65), the C allele at polymorphism rs17582919 (SEQ ID NO: 66), the C allele at polymorphism rs10815393 (SEQ ID NO: 67), the C allele at polymorphism rs12339348 (SEQ ID NO: 68). The polymorphisms include at least one of the following: G allele at polymorphism rs10815392 (SEQ ID NO: 67), C allele at polymorphism rs72689561 (SEQ ID NO: 69), C allele at polymorphism rs7038893 (SEQ ID NO: 70), T allele at polymorphism rs112935616 (SEQ ID NO: 71), T allele at polymorphism rs10815376 (SEQ ID NO: 72), A allele at polymorphism rs12551268 (SEQ ID NO: 73), and G allele at polymorphism rs2006682 (SEQ ID NO: 74).

[0207] In some examples, the patient's genotype is at least one of the following: a T allele at polymorphism rs10975507 (SEQ ID NO: 60) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; a G allele at polymorphism rs10975504 (SEQ ID NO: 61) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; a C allele at polymorphism rs10815393 (SEQ ID NO: 62) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; a T allele at polymorphism rs12339348 (SEQ ID NO: 63) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; a G allele at polymorphism rs7035413 (SEQ ID NO: 64) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; a C allele at polymorphism rs17498196 (SEQ ID NO: 65) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith; the C allele of polymorphism rs72689561 (SEQ ID NO: 69) or at least one equivalent allele of a polymorphism in linkage disequilibrium therewith; the C allele of polymorphism rs7038893 (SEQ ID NO: 70) or at least one equivalent allele of a polymorphism in linkage disequilibrium therewith; the C allele of polymorphism rs7582919 (SEQ ID NO: 66) or at least one equivalent allele of a polymorphism in linkage disequilibrium therewith; the G allele of polymorphism rs10815391 (SEQ ID NO: 67) or at least one equivalent allele of a polymorphism in linkage disequilibrium therewith; the C allele of polymorphism rs10815392 (SEQ ID NO: 68) or at least one equivalent allele of a polymorphism in linkage disequilibrium therewith; the C allele of polymorphism rs72689561 (SEQ ID NO: 69) or at least one equivalent allele of a polymorphism in linkage disequilibrium therewith; the C allele of polymorphism rs7038893 (SEQ ID NO: 70) or at least one equivalent allele of a polymorphism in linkage disequilibrium therewith; and the T allele of polymorphism rs112935616 (SEQ ID NO: 71) or at least one equivalent allele of a polymorphism in linkage disequilibrium therewith.

[0208] In some examples, the patient's genotype is a T allele at polymorphism rs10975507 (SEQ ID NO: 60), a G allele at polymorphism rs10975504 (SEQ ID NO: 61), a C allele at polymorphism rs10815393 (SEQ ID NO: 62), a T allele at polymorphism rs12339348 (SEQ ID NO: 63), a G allele at polymorphism rs7035413 (SEQ ID NO: 64), a C allele at polymorphism rs17498196 (SEQ ID NO: 65), a C allele at polymorphism rs1 The polymorphism comprises at least one allele selected from the C allele at 7582919 (SEQ ID NO: 66), the G allele at polymorphism rs10815391 (SEQ ID NO: 67), the C allele at polymorphism rs10815392 (SEQ ID NO: 68), the C allele at polymorphism rs72689561 (SEQ ID NO: 69), the C allele at polymorphism rs7038893 (SEQ ID NO: 70), and the T allele at polymorphism rs112935616 (SEQ ID NO: 71).

[0209] In some examples, the patient's genotype is one of two T alleles at polymorphism rs10975507 (SEQ ID NO: 60) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two G alleles at polymorphism rs10975504 (SEQ ID NO: 61) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two C alleles at polymorphism rs10815393 (SEQ ID NO: 62) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two T alleles at polymorphism rs12339348 (SEQ ID NO: 63) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two G alleles at polymorphism rs7035413 (SEQ ID NO: 64) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith, two C alleles at polymorphism rs17498196 (SEQ ID NO: 65 ... The two alleles include two alleles of a polymorphism selected from two C alleles in s17582919 (SEQ ID NO: 66) or two equivalent alleles in a polymorphism in linkage disequilibrium therewith, two G alleles in polymorphism rs10815391 (SEQ ID NO: 67) or two equivalent alleles in a polymorphism in linkage disequilibrium therewith, two C alleles in polymorphism rs10815392 (SEQ ID NO: 68) or two equivalent alleles in a polymorphism in linkage disequilibrium therewith, two C alleles in polymorphism rs72689561 (SEQ ID NO: 69) or two equivalent alleles in a polymorphism in linkage disequilibrium therewith, two C alleles in polymorphism rs7038893 (SEQ ID NO: 70) or two equivalent alleles in a polymorphism in linkage disequilibrium therewith, and two alleles of a polymorphism selected from two T alleles in polymorphism rs112935616 (SEQ ID NO: 71) or two equivalent alleles in a polymorphism in linkage disequilibrium therewith.

[0210] In some examples, the patient's genotype is two T alleles at polymorphism rs10975507 (SEQ ID NO: 60), two G alleles at polymorphism rs10975504 (SEQ ID NO: 61), two C alleles at polymorphism rs10815393 (SEQ ID NO: 62), two T alleles at polymorphism rs12339348 (SEQ ID NO: 63), two G alleles at polymorphism rs7035413 (SEQ ID NO: 64), two C alleles at polymorphism rs17498196 (SEQ ID NO: 65 ... The polymorphism includes two alleles at polymorphisms selected from two C alleles at rs17582919 (sequence number 66), two G alleles at polymorphism rs10815391 (sequence number 67), two C alleles at polymorphism rs10815392 (sequence number 68), two C alleles at polymorphism rs72689561 (sequence number 69), two C alleles at polymorphism rs7038893 (sequence number 70), and two T alleles at polymorphism rs112935616 (sequence number 71).

[0211] In some examples, the patient's genotype comprises at least one T allele at polymorphism rs10975507 (SEQ ID NO: 60) or at least one equivalent allele at a polymorphism in linkage disequilibrium therewith.

[0212] In some examples, the patient's genotype includes at least one T allele at polymorphism rs10975507 (SEQ ID NO: 60).

[0213] In some instances, the patient's genotype comprises two T alleles at polymorphism rs10975507 (SEQ ID NO: 60) or two equivalent alleles at a polymorphism in linkage disequilibrium therewith.

[0214] In some examples, the patient's genotype includes two T alleles at polymorphism rs10975507 (SEQ ID NO: 60).

[0215] In some examples, the patient's genotype includes one or two C alleles at polymorphism rs7038893 (SEQ ID NO: 70) or one or two equivalent alleles at a polymorphism in linkage disequilibrium therewith.

[0216] In some examples, the patient's genotype includes one or two C alleles at polymorphism rs7038893 (SEQ ID NO: 70).

[0217] Cluster 4 In some examples, the patient's genotype does not include at least one polymorphism selected from the C allele at polymorphism rs370820588 (SEQ ID NO: 75), the C allele at polymorphism rs143215670 (SEQ ID NO: 76), the A allele at polymorphism rs343478 (SEQ ID NO: 77), the G allele at polymorphism rs10118776 (SEQ ID NO: 78), the C allele at polymorphism rs146597587 (SEQ ID NO: 79), the T allele at polymorphism rs10975519 (SEQ ID NO: 80), and the G allele at polymorphism rs10815381 (SEQ ID NO: 81).

[0218] In one example, the patient's genotype does not include at least one of each of the following polymorphisms: the C allele at polymorphism rs370820588 (SEQ ID NO: 75), the C allele at polymorphism rs143215670 (SEQ ID NO: 76), the A allele at polymorphism rs343478 (SEQ ID NO: 77), the G allele at polymorphism rs10118776 (SEQ ID NO: 78), the C allele at polymorphism rs146597587 (SEQ ID NO: 79), the T allele at polymorphism rs10975519 (SEQ ID NO: 80), and the G allele at polymorphism rs10815381 (SEQ ID NO: 81).

[0219] In one example, the patient's genotype does not include two polymorphisms selected from two C alleles at polymorphism rs370820588 (SEQ ID NO: 75), two C alleles at polymorphism rs143215670 (SEQ ID NO: 76), two A alleles at polymorphism rs343478 (SEQ ID NO: 77), two G alleles at polymorphism rs10118776 (SEQ ID NO: 78), two C alleles at polymorphism rs146597587 (SEQ ID NO: 79), two T alleles at polymorphism rs10975519 (SEQ ID NO: 80), and two G alleles at polymorphism rs10815381 (SEQ ID NO: 81).

[0220] In one example, the patient's genotype does not include the following polymorphisms: two C alleles at polymorphism rs370820588 (SEQ ID NO: 75), two C alleles at polymorphism rs143215670 (SEQ ID NO: 76), two A alleles at polymorphism rs343478 (SEQ ID NO: 77), two G alleles at polymorphism rs10118776 (SEQ ID NO: 78), two C alleles at polymorphism rs146597587 (SEQ ID NO: 79), two T alleles at polymorphism rs10975519 (SEQ ID NO: 80), and two G alleles at polymorphism rs10815381 (SEQ ID NO: 81).

[0221] In some examples, the diagnostic methods disclosed herein further comprise administering to the patient an IL-33 axis binding antagonist.

[0222] SNP combinations The above treatment and diagnostic methods contemplate cases where a patient's genotype may include a combination of cluster 1, 2 or 3 polymorphisms.

[0223] Suitably, where the patient's genotype has been determined to comprise a Cluster 2 polymorphism, the patient's genotype may be further determined to comprise at least one allele of a Cluster 3 polymorphism as defined in Table 2 or as set out in the specific examples above for a Cluster 3 polymorphism. Additionally or alternatively, the patient's genotype may be further determined to comprise at least one allele of a Cluster 1 polymorphism as defined in Table 3 or as set out in the specific examples above for a Cluster 1 polymorphism.

[0224] Suitably, where the patient's genotype has been determined to comprise a Cluster 3 polymorphism, the patient's genotype may be further determined to comprise at least one allele of a Cluster 2 polymorphism as defined in Table 1 or as set out in the specific examples above for Cluster 2 polymorphisms. Additionally or alternatively, the patient's genotype may be further determined to comprise at least one allele of a Cluster 1 polymorphism as defined in Table 3 or as set out in the specific examples above for Cluster 1 polymorphisms.

[0225] If the patient's genotype has been determined to include a Cluster 1 polymorphism, the patient's genotype may be further determined to include at least one allele of a Cluster 2 polymorphism as defined in Table 1 or as described in the specific examples above for a Cluster 2 polymorphism. Additionally or alternatively, the patient's genotype may be further determined to include at least one allele of a Cluster 3 polymorphism as defined in Table 2 or as described in the specific examples above for a Cluster 3 polymorphism.

[0226] SNP detection In some examples, the therapeutic and diagnostic methods disclosed herein involve determining a patient's genotype at one or more Cluster 1, 2, or 3 polymorphisms (e.g., those listed in Tables 1-3). Detection techniques for assessing nucleic acids for the presence of SNPs include procedures well known in the field of molecular genetics. Many, but not all, methods involve nucleic acid amplification. Ample guidance for performing amplification is provided in the art. Exemplary references include manuals such as Erlich, ed., PCR Technology: Principles and Applications for DNA Amplification, Freeman Press, 1992; Innis et al., eds., PCR Protocols: A Guide to Methods and Applications, Academic Press, 1990; Ausubel, ed., Current Protocols in Molecular Biology, 1994-1999 (including supplemental updates through April 2004); and Sambrook et al., eds., Molecular Cloning, A Laboratory Manual, 2001. General methods for detecting single nucleotide polymorphisms are disclosed in Kwok, ed., Single Nucleotide Polymorphisms: Methods and Protocols, Humana Press, 2003.

[0227] Methods typically employ a PCR step, although other amplification protocols can also be used. Suitable amplification methods include ligase chain reaction (see, e.g., Wu et al. Genomics 4:560-569, 1988); strand displacement assay (see, e.g., Walker et al. Proc. Nat. Acad. Sci. USA 89:392-396, 1992; U.S. Pat. No. 5,455,166); and several transcription-based amplification systems (including those described in U.S. Pat. Nos. 5,437,990, 5,409,818, and 5,399,491); transcription-associated amplification systems (TAS) (Kwoh et al. Proc. Nat. Acad. Sci. USA 86:1173-1177, 1989); and self-sustained sequence replication (3SR) (Guatelli et al. Proc. Nat. Acad. Sci. USA 87:1874-1878, 1990; WO 1992 / 08800). Alternatively, methods for amplifying probes to detectable levels, such as Qβ-replicase amplification (Kramer et al. Nature 339:401-402, 1989; Lomeli et al. Clin. Chern. 35:1826-1831, 1989), can be used. A review of known amplification methods is provided, for example, by Abramson et al. Curr. Opin. Biotech. 4:41-47, 1993.

[0228] Detection of an individual's genotype, haplotype, SNP, microsatellite, or other polymorphism can be performed using oligonucleotide primers and / or probes. Oligonucleotides can be prepared by any suitable method, usually chemical synthesis. Oligonucleotides can be synthesized using commercially available reagents and equipment. Alternatively, they can be purchased through commercial sources. Methods for synthesizing oligonucleotides are well known in the art (see, for example, Narang et al. Meth. Enzymol. 68:90-99, 1979; Brown et al. Meth. Enzymol. 68:109-151, 1979; Beaucage et al. Tetra. Lett. 22:1859-1862, 1981; and the solid support method of U.S. Pat. No. 4,458,066). In addition, modifications to the above-mentioned synthesis methods can be used to desirably affect enzyme behavior on synthetic oligonucleotides. For example, the incorporation of modified phosphodiester linkages (e.g., phosphorothioate, methylphosphonate, phosphoramidate, or boranophosphate) or linkages other than phosphorous derivatives into oligonucleotides can be used to prevent cleavage at selected sites. In addition, the use of 2'-amino modified sugars tends to favor displacement over digestion of the oligonucleotide when hybridized to a nucleic acid that is also a template for the synthesis of a new nucleic acid strand.

[0229] The genotype of an individual (e.g., a patient suffering from or at risk of an IL-33-mediated disorder, such as asthma or pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis)) can be determined using many detection methods well known in the art. Most assays require one of several common protocols: hybridization using allele-specific oligonucleotides, primer extension, allele-specific ligation, sequencing, or electrophoretic separation techniques, such as single-strand conformation polymorphism analysis (SSCP) and heteroduplex analysis. Exemplary assays include 5'-nuclease assays, template-specific dye-terminator incorporation, molecular beacon allele-specific oligonucleotide assays, single-base extension assays, and SNP scoring by real-time pyrophosphate sequencing. Analysis of amplified sequences can be performed using a variety of techniques, such as microchips, fluorescence polarization assays, and MALDI-TOF (matrix-assisted laser desorption / ionization-time of flight) mass spectrometry. Two additional methods that can be used are assays based on invasive cleavage by flap nucleases and approaches using padlock probes.

[0230] Determining the presence or absence of a particular allele is generally performed by analyzing a nucleic acid sample obtained from the individual being analyzed. In many cases, the nucleic acid sample contains genomic DNA. Genomic DNA is typically obtained from a blood sample, but can also be obtained from other cells or tissues.

[0231] Samples can be taken from patients suspected of or diagnosed with an IL-33-mediated disorder (and therefore may require treatment) or from normal individuals not suspected of having any disorder. To determine genotype, patient samples, such as those containing cells, or nucleic acids produced by these cells, can be used in the methods disclosed herein. Bodily fluids or secretions useful as samples in the present disclosure include, for example, blood, urine, saliva, feces, pleural effusion, lymphatic fluid, sputum, ascites, prostatic fluid, cerebrospinal fluid (CSF), or any other bodily secretion or derivative thereof. The term blood is meant to include whole blood, plasma, serum, or any derivative of blood. Sample nucleic acids for use in the methods described herein can be obtained from any cell type or tissue of a subject. For example, a subject's bodily fluid (e.g., blood) can be obtained by known techniques. Alternatively, nucleic acid testing can be performed on a dried sample (e.g., hair or skin).

[0232] Samples can be frozen, fresh, fixed (e.g., formalin-fixed), centrifuged, and / or embedded (e.g., paraffin-embedded), etc. Of course, cell samples can be subjected to a variety of well-known post-collection preparation and preservation techniques (e.g., nucleic acid and / or protein extraction, fixation, preservation, freezing, ultrafiltration, concentration, evaporation, centrifugation, etc.) prior to assessing the genotype in the sample. Similarly, biopsies can also be subjected to post-collection preparation and preservation techniques, such as fixation.

[0233] Frequently used techniques for analyzing nucleic acid samples to detect SNPs that are useful in this disclosure are briefly described below, although any method known in the art for detecting the presence of single base substitutions can be used in the present invention.

[0234] Allele-specific hybridization This technique, commonly referred to as allele-specific oligonucleotide hybridization (ASO) (e.g., Stoneking et al. Am. J. Hum. Genet. 48:70-382, 1991; Saiki et al. Nature 324, 163-166, 1986; EP 235,726; and WO 1989 / 11548), relies on distinguishing between two DNA molecules that differ by a single base by hybridizing an oligonucleotide probe specific for one of the variants to an amplification product obtained from amplification of a nucleic acid sample. This method typically uses short oligonucleotides, e.g., 15-20 bases in length. The probes are designed to differentially hybridize to one variant relative to another. Principles and guidelines for designing such probes are available in the art, for example, in the references cited herein. Hybridization conditions must be sufficiently stringent so that there is a substantial difference in hybridization intensity between alleles, generating a substantially binary response, whereby the probe hybridizes to only one of the alleles. Some probes are designed to hybridize to a segment of target DNA such that the polymorphic site is aligned with the central position of the probe (e.g., position 7 of a 15-base oligonucleotide; either position 8 or 9 of a 16-base oligonucleotide), although this design is not required.

[0235] The amount and / or presence of an allele can be determined by measuring the amount of allele-specific oligonucleotide that hybridizes to a sample. Typically, the oligonucleotide is labeled with a label, such as a fluorescent label. For example, the allele-specific oligonucleotide is applied to an immobilized oligonucleotide representing the SNP sequence. After stringent hybridization and washing conditions, the fluorescence intensity of each SNP oligonucleotide is measured.

[0236] The nucleotide present at a polymorphic site can be identified by hybridizing, under sequence-specific hybridization conditions, an oligonucleotide probe or primer that is exactly complementary to one of the polymorphic alleles in the region encompassing the polymorphic site. The sequence to which the probe or primer hybridizes and the sequence-specific hybridization conditions are selected so that a single mismatch at the polymorphic site sufficiently destabilizes the hybridization duplex, so that the duplex effectively does not form. Thus, under sequence-specific hybridization conditions, a stable duplex is formed only between the probe or primer and the exactly complementary allele sequence. Therefore, oligonucleotides about 10 to about 35 nucleotides in length, typically about 15 to about 35 nucleotides in length, that are exactly complementary to the allele sequence in the region encompassing the polymorphic site are within the scope of the present invention.

[0237] In another example, the nucleotide present at the polymorphic site is identified by hybridizing with an oligonucleotide that is substantially complementary to one of the SNP alleles in the region encompassing the polymorphic site and is exactly complementary to the allele at the polymorphic site under sufficiently stringent hybridization conditions.Since the mismatch occurring at the non-polymorphic site is a mismatch with both allele sequences, the difference in the number of mismatches between the duplex formed with the target allele sequence and the duplex formed with the corresponding non-target allele sequence is the same as when an oligonucleotide that is exactly complementary to the target allele sequence is used.In this case, the hybridization conditions are relaxed enough to allow the formation of a stable duplex with the target sequence, while maintaining sufficient stringency to prevent the formation of a stable duplex with non-target sequences.Under such sufficiently stringent hybridization conditions, a stable duplex is only formed between the probe or primer and the target allele. Therefore, it is possible to detect oligonucleotides of about 10 to about 35 nucleotides in length, usually about 15 to about 35 nucleotides in length, which are substantially complementary to the allelic sequence in the region encompassing the polymorphic site and are strictly complementary to the allelic sequence of the polymorphic site.

[0238] In assay formats where optimization of hybridization conditions is limited, it may be desirable to use substantially complementary, rather than strictly complementary, oligonucleotides. For example, in a typical multi-target immobilized oligonucleotide assay format, probes or primers for each target are immobilized on a single solid support. Hybridization occurs simultaneously by contacting the solid support with a solution containing target DNA. Because all hybridizations occur under identical conditions, hybridization conditions cannot be optimized separately for each probe or primer. If the assay format does not allow adjustment of hybridization conditions, incorporation of mismatches into the probe or primer can be used to adjust duplex stability. The effect of specific mismatches introduced on duplex stability is well known, and duplex stability can be routinely estimated or experimentally determined, as described above. Appropriate hybridization conditions, which depend on the exact size and sequence of the probe or primer, can be selected empirically using the guidelines provided herein and well known in the art. The use of oligonucleotide probes or primers to detect single base pair differences in sequence is described, for example, in Conner et al. Proc. Nat. Acad. Sci. USA 80:278-282, 1983 and U.S. Pat. Nos. 205,468,613 and 5,604,099.

[0239] The proportional change in stability between a perfectly matched hybridization duplex and a single-base mismatched hybridization duplex depends on the length of the hybridized oligonucleotide. Duplexes formed with shorter probe sequences are proportionally more destabilized by the presence of mismatches. Oligonucleotides about 15 to about 35 nucleotides in length are often used for sequence-specific detection. Furthermore, because the ends of a hybridized oligonucleotide undergo continuous random dissociation and reannealing due to thermal energy, mismatches at either end do not destabilize the hybridization duplex as much as mismatches occurring internally. To discriminate between single base pair changes in a target sequence, a probe sequence is selected that hybridizes to the target sequence so that the polymorphic site occurs in the internal region of the probe.

[0240] The above criteria for selecting a probe sequence that hybridizes to a specific allele apply to the hybridizing region of the probe, i.e., the portion of the probe that is involved in hybridization with the target sequence. Probes can be linked to additional nucleic acid sequences, such as poly-T tails, that are used to immobilize the probe without significantly altering the hybridization properties of the probe. Those skilled in the art will recognize that, when used in the methods of the present invention, a probe that is linked to an additional nucleic acid sequence that is not complementary to the target sequence, i.e., that is not involved in hybridization, is essentially equivalent to an unlinked probe.

[0241] Assay formats suitable for detecting hybrids formed between a probe and a target nucleic acid sequence in a sample are known in the art and include immobilized target (dot blot) and immobilized probe (reverse dot blot or line blot) assay formats. Dot blot and reverse dot blot assay formats are described in U.S. Patent Nos. 5,310,893, 5,451,512, 5,468,613, and 5,604,099.

[0242] In the dot blot format, amplified target DNA is immobilized on a solid support such as a nylon membrane, the membrane-target complex is incubated with a labeled probe under appropriate hybridization conditions, unhybridized probe is removed by washing under appropriately stringent conditions, and the membrane is monitored for the presence of bound probe.

[0243] In the reverse dot blot (or line blot) format, the probe is immobilized on a solid support such as a nylon membrane or a microtiter plate. The target DNA is labeled during amplification, typically by incorporation of labeled primers. One or both of the primers can be labeled. The membrane-probe complex is incubated with labeled, amplified target DNA under appropriate hybridization conditions, unhybridized target DNA is removed by washing under appropriately stringent conditions, and the membrane is monitored for the presence of bound target DNA.

[0244] An allele-specific probe specific to one polymorphic variant is often used in combination with an allele-specific probe for another polymorphic variant. The probes can be immobilized on a solid support, and the target sequence in an individual is analyzed using both probes simultaneously. Examples of nucleic acid arrays are described in WO 95 / 11995. The same array or different arrays can be used to analyze characterized polymorphisms. WO 95 / 11995 also describes subarrays optimized for detecting variant forms of previously characterized polymorphisms. Such subarrays can be used to detect the presence of the polymorphisms described herein.

[0245] Allele-specific primers Polymorphisms are also commonly detected using allele-specific amplification or primer extension methods. These reactions typically involve the use of primers designed to specifically target polymorphisms via mismatches at the 3' end of the primer. The presence of a mismatch affects the ability of a polymerase to extend the primer if the polymerase lacks error-correcting activity. For example, to detect an allele sequence using an allele-specific amplification or extension-based method, a primer complementary to one allele of a polymorphism is designed so that its 3'-terminal nucleotide hybridizes at the polymorphic position. The presence of a specific allele can be determined by the primer's ability to initiate extension. If the 3' end is mismatched, extension is prevented.

[0246] In some instances, the primer is used in combination with a second primer during the amplification reaction. The second primer hybridizes at a site unrelated to the polymorphic position. Amplification proceeds from the two primers, resulting in a detectable product indicating the presence of a specific allele form. Methods based on allele-specific amplification or extension are described, for example, in WO 93 / 22456, U.S. Patent Nos. 5,137,806, 5,595,890, 5,639,611, and 4,851,331.

[0247] Using allele-specific amplification-based genotyping, allele identification requires only the detection of the presence or absence of an amplified target sequence. Methods for detecting an amplified target sequence are well known in the art. For example, gel electrophoresis and probe hybridization assays, as described, are often used to detect the presence of nucleic acids.

[0248] In another probeless method, amplified nucleic acids are detected by monitoring the increase in the total amount of double-stranded DNA in the reaction mixture, and this method is described, for example, in U.S. Patent No. 5,994,056 and European Patent Applications Nos. 487,218 and 512,334. Detection of double-stranded target DNA relies on the increased fluorescence that various DNA-binding dyes, such as SYBR Green, exhibit when bound to double-stranded DNA.

[0249] As will be understood by those skilled in the art, allele-specific amplification methods can be carried out in a reaction using multiple allele-specific primers to target specific alleles. Primers for such multiplex applications are generally labeled with distinguishable labels or selected so that the amplification products resulting from the alleles are distinguishable by size. Thus, for example, multiple alleles in a single sample can be identified using a single amplification by gel analysis of the amplification products.

[0250] As with allele-specific probes, the allele-specific oligonucleotide primers may be exactly complementary to one of the polymorphic alleles in the hybridizing region, or may have several mismatches at positions other than the 3' end of the oligonucleotide (where the mismatches occur at non-polymorphic sites in both allele sequences).

[0251] Detectable probes 5'-Nuclease Assay Probe Genotyping can also be performed using the "TAQMAN®" or "5'-nuclease assay," as described in U.S. Patent Nos. 5,210,015, 5,487,972, and 5,804,375; and Holland et al., Proc. Nat. Acad. Sci. USA 88:7276-7280, 1988. In the TAQMAN® assay, a labeled detection probe that hybridizes within the amplified region is added to the amplification reaction. The probe is modified to prevent it from acting as a primer for DNA synthesis. Amplification is performed using a DNA polymerase with 5'-3' exonuclease activity. During each synthesis step of amplification, any probe that hybridizes to the target nucleic acid downstream of the extended primer is degraded by the 5'-3' exonuclease activity of the DNA polymerase. Thus, synthesis of new target strands also results in degradation of the probe, and the accumulation of degradation products provides an indication of synthesis of the target sequence.

[0252] The hybridization probe can be an allele-specific probe that distinguishes between SNP alleles. Alternatively, the method can be performed using allele-specific primers and a labeled probe that binds to the amplification product.

[0253] Any method suitable for detecting degradation products can be used in 5'-nuclease assays. Often, the detection probe is labeled with two fluorescent dyes, one of which can quench the fluorescence of the other dye. The dyes are attached to the probe, usually at the 5' end and the other at an internal site, resulting in quenching when the probe is unhybridized and cleavage of the probe between the two dyes by the 5'-3' exonuclease activity of DNA polymerase. Amplification cleaves the probe between the dyes, simultaneously eliminating quenching and increasing the observable fluorescence from the initially quenched dye. The accumulation of degradation products is monitored by measuring the increase in reaction fluorescence. U.S. Pat. Nos. 5,491,063 and 5,571,673 describe other methods for detecting probe degradation concomitant with amplification.

[0254] Secondary structure probes Probes that are detectable upon secondary structure change are also suitable for detecting polymorphisms, including SNPs. Exemplary secondary structure or stem-loop structure probes include molecular beacons or SCORPION® primer / probes. Molecular beacon probes are single-stranded oligonucleic acid probes that can form hairpin structures, in which a fluorophore and a quencher are typically located at both ends of the oligonucleotide. Short complementary sequences at either end of the probe allow the formation of an intramolecular stem, allowing the fluorophore and quencher to be in close proximity. The loop portion of the molecular beacon is complementary to the target nucleic acid of interest. When the probe binds to the target nucleic acid of interest, a hybrid is formed that separates the stem. This causes a conformational change that moves the fluorophore and quencher away from each other, resulting in a stronger fluorescent signal. Molecular beacon probes are highly sensitive to slight sequence variations in the probe target (see, for example, Tyagi et al. Nature Biotech. 14:303-308, 1996; Tyagi et al. Nature Biotech. 16:49-53, 1998; Piatek et al. Nature Biotech. 16:359-363, 1998; Marras et al. Genetic Analysis: Biomolecular Engineering 14:151-156, 1999; Tapp et al. BioTechniques 28:732-738, 2000). SCORPION® primer / probes contain a stem-loop structure probe covalently linked to a primer.

[0255] DNA sequencing and single base extension SNPs can also be detected by direct sequencing, including, for example, methods based on dideoxy sequencing as well as other methods such as Maxam-Gilbert sequences (see, e.g., Sambrook and Russell, supra).

[0256] Other detection methods include PYROSEQUENCING™ of oligonucleotide-length products. Such methods often use amplification techniques such as PCR. For example, in pyrosequencing, a sequencing primer is hybridized to a single-stranded PCR-amplified DNA template and incubated with the enzymes DNA polymerase, ATP sulfurylase, luciferase, and apyrase, and the substrates adenosine 5' phosphosulfate (APS) and luciferin. The first of four deoxynucleotide triphosphates (dNTPs) is added to the reaction. DNA polymerase catalyzes the incorporation of a deoxynucleotide triphosphate into the DNA strand if it is complementary to a base in the template strand. Each incorporation event is accompanied by the release of pyrophosphate (PPi), an amount equimolar to the amount of incorporated nucleotide. ATP sulfurylase quantitatively converts PPi to ATP in the presence of APS. This ATP triggers the luciferase-mediated conversion of luciferin to oxyluciferin, thereby producing visible light in an amount proportional to the amount of ATP. The light produced by the luciferase-catalyzed reaction is detected by a charge-coupled device (CCD) camera and seen as a peak in the PYROGRAM™. Each light signal is proportional to the number of nucleotides incorporated. The nucleotide-degrading enzyme apyrase sequentially degrades unincorporated dNTPs and excess ATP. Once degradation is complete, another dNTP is added.

[0257] Another similar method for characterizing SNPs does not require the use of full PCR, but typically uses only primer extension with a single fluorescently labeled dideoxyribonucleic acid molecule (ddNTP) that is complementary to the nucleotide under investigation. The nucleotide at the polymorphic site can be identified by detecting the fluorescently labeled, one-base extended primer (e.g., Kobayashi et al., Mol. Cell. Probes, 9:175-182, 1995).

[0258] Electrophoresis Amplification products generated using the polymerase chain reaction can be analyzed using denaturing gradient gel electrophoresis. Different alleles can be identified based on the different sequence-dependent melting properties and electrophoretic migration of DNA in solution (see, e.g., Erlich, ed., PCR Technology, Principles and Applications for DNA Amplification, W.H. Freeman and Co., 1992).

[0259] The identification of microsatellite polymorphisms can be carried out using capillary electrophoresis. Capillary electrophoresis can easily identify the number of repeats in a specific microsatellite allele. The application of capillary electrophoresis to the analysis of DNA polymorphisms is well known to those skilled in the art (see, for example, Szantai et al. J Chromatogr A.1 079(1-2):41-9, 2005; Bjorheim et al. Electrophoresis 26(13):2520-30, 2005 and Mitchelson, Mol. Biotechnol. 24(1):41-68, 2003).

[0260] The identity of allelic variants can also be determined by analyzing the behavior of nucleic acids containing polymorphic regions in polyacrylamide gels containing a denaturing gradient, which is assayed using denaturing gradient gel electrophoresis (DGGE) (see, for example, Myers et al. Nature 313:495-498, 1985). When DGGE is used as the analysis method, DNA is modified to ensure complete denaturation, for example, by adding a GC clamp of about 40 bp of high-melting-point GC-rich DNA by PCR. In some instances, a temperature gradient can be used instead of a denaturing gradient to reveal differences in the mobility of control and sample DNA (see, for example, Rosenbaum et al. Biophys. Chem. 265:1275, 1987).

[0261] Single-strand conformation polymorphism analysis Alleles of a target sequence can be distinguished using single-strand conformation polymorphism analysis, which identifies base differences by changes in the electrophoretic mobility of single-stranded PCR products, as described, for example, in Orita et al. Proc. Nat. Acad. Sci. 86, 2766-2770, 1989; Cotton Mutat. Res. 285:125-144, 1993; and Hayashi Genet. Anal. Tech. Appl. 9:73-79, 1992. Amplified PCR products can be generated as described above and heated or otherwise denatured to form single-stranded amplification products. Single-stranded nucleic acids can refold or form secondary structures that depend in part on the base sequence. The different electrophoretic mobilities of single-stranded amplification products can be correlated with differences in base sequence between target alleles, and the resulting change in electrophoretic mobility allows for the detection of even single-base changes. DNA fragments can be labeled or detected with labeled probes. The sensitivity of the assay can be enhanced by using RNA (rather than DNA), whose secondary structure is more sensitive to changes in sequence. In another example, methods utilize heteroduplex analysis to separate double-stranded heteroduplex molecules based on changes in electrophoretic mobility (see, e.g., Keen et al. Trends Genet. 7:5-10, 1991).

[0262] Methods for detecting SNPs often use labeled oligonucleotides. Oligonucleotides can be labeled by incorporating a label detectable by spectroscopic, photochemical, biochemical, immunochemical, or chemical means. Useful labels include fluorescent dyes, radioactive labels, e.g., 32 Labeling techniques include P, electron-dense reagents, enzymes (e.g., peroxidase or alkaline phosphatase), biotin, or haptens and proteins for which antisera or monoclonal antibodies are available. Labeling techniques are well known in the art (see, e.g., Current Protocols in Molecular Biology, supra; Sambrook et al., supra).

[0263] IL-33 axis binding antagonists The therapeutic and diagnostic methods disclosed herein identify subjects who can be preferentially treated with an IL-33 axis binding antagonist. An "IL-33 axis binding antagonist" refers to a molecule that inhibits the interaction of an IL-33 axis binding partner with one or more of its binding partners. As used herein, IL-33 axis binding antagonists include IL-33 binding antagonists, ST2 binding antagonists, and IL-1RAcP binding antagonists.

[0264] Exemplary IL-33 binding antagonists include 33_640087-7B (described in WO 2016 / 156440), ANB020, also known as etokimab (described in WO 2015 / 106080), 9675P (described in U.S. Patent Application Publication No. 2014 / 0271658), A25-3H04 (described in U.S. Patent Application Publication No. 2017 / 0283494), Ab43 (described in WO 2018 / 081075), IL33-158 (described in U.S. Patent Application Publication No. 2018 / 0037644), 10C12.38.H6.87Y.581 Anti-IL-33 antibodies or antigen-binding fragments thereof include IgG4 (as described in WO2016 / 077381) or binding fragments thereof. Other exemplary anti-IL-33 antibodies or antigen-binding fragments thereof include any of the other anti-IL-33 antibodies described in WO2016 / 156440, WO2015 / 106080, US2014 / 0271658, US2017 / 0283494, WO2018 / 081075, US2018 / 0037644, or WO2016 / 077381 (all of which are incorporated by reference herein).

[0265] Other exemplary IL-33 axis-binding antagonists include polypeptides that bind to IL-33 and / or its receptor (ST-2) or co-receptor (IL1-RAcP) and block the ligand-receptor interaction (e.g., ST2-Fc proteins or soluble ST2 or derivatives thereof, such as those described in WO 2013 / 173761; WO 2013 / 165894; or WO 2014 / 152195, each of which is incorporated by reference in its entirety).

[0266] Other exemplary IL-33 axis binding antagonists also include anti-ST-2 antibodies or antigen-binding fragments thereof (e.g., AMG-282 (Amgen) or STLM15 (Janssen), or any of the anti-ST2 antibodies described in WO 2013 / 173761 or WO 2013 / 165894, each of which is incorporated by reference in its entirety).

[0267] Other exemplary IL-33 axis binding antagonists include IL-33 receptor-based ligand traps, such as those described in WO 2018 / 102597, which is incorporated herein by reference.

[0268] In one example, the IL-33 axis binding antagonist is a binding molecule. Preferably, the binding molecule can be an antibody or an antigen-binding fragment thereof.

[0269] Preferably, the binding molecule specifically binds to IL-33. Such binding molecules are also referred to as "IL-33 binding molecules" or "anti-IL-33 binding molecules." Preferably, the binding molecule specifically binds to IL-33 and inhibits or attenuates IL-33 activity.

[0270] Preferably, the IL-33 binding molecule specifically binds to reduced IL-33, oxidized IL-33, or both reduced and oxidized IL-33.

[0271] Suitably, the binding molecule is capable of attenuating or inhibiting IL-33 activity by binding to reduced or oxidized IL-33. Suitably, where the binding molecule inhibits or attenuates the activity of reduced IL-33 and the activity of oxidized IL-33, this is achieved by binding to reduced IL-33 (i.e. by binding to reduced IL-33).

[0272] Suitably, the binding molecule inhibits or attenuates the activity of both redIL-33 and oxIL-33, thereby inhibiting or attenuating both ST2 signalling and RAGE signalling.

[0273] Preferably, the binding molecules are 5×10 -2 Under M, 10 -2 Less than M, 5 x 10 -3 Under M, 10 -3 Less than M, 5 x 10 -4 Under M, 10 -4 Less than M, 5 x 10 -5 Under M, 10 -5 Less than M, 5 x 10 -6 Under M, 10 -6 Less than M, 5 x 10 -7 Under M, 10 -7 Less than M, 5 x 10 -8 Under M, 10 -8 Less than M, 5 x 10 -9 Under M, 10 -9 Less than M, 5 x 10 -10 Under M, 10 -10 Less than M, 5 x 10 -11 Under M, 10 -11 Less than M, 5 x 10 -12 Under M, 10 -12 Less than M, 5 x 10 -13 Under M, 10 -13 Less than M, 5 x 10 -14 Under M, 10 -14 Less than M, 5 x 10 -15 Less than M or 10 -15 It can specifically bind to redIL-33 with a binding affinity (Kd) of less than M. Preferably, the binding affinity to redIL-33 is 5×10 -14The binding affinity is less than 0.05 pM (i.e., 0.05 pM). Preferably, the binding affinity is measured using a Kinetic Exclusion Assay (KinExA) or BIACORE™, preferably using KinExA, using a protocol such as that described in WO 2016 / 156440, which is incorporated herein by reference in its entirety (see, e.g., Example 11). Binding molecules that bind redIL-33 with this binding affinity have been shown to bind tightly enough to prevent dissociation of the binding molecule / redIL-33 complex within a biologically relevant timescale. Without wishing to be bound by theory, it is believed that this binding strength prevents release of the antigen prior to degradation of the binding molecule / antigen complex in vivo, minimizing any IL-33-dependent activity associated with release of IL-33 from the binding complex.

[0274] Preferably, the binding molecule is 10 3 M -1 seconds -1 That's it, 5 x 10 3 M -1 seconds -1 That's it, 10 4 M -1 seconds -1 or more or 5 x 10 4 M -1 seconds -1 For example, the binding molecules of the present disclosure may specifically bind to redIL-33 with an on-rate (k(on)) of 10 or greater. 5 M -1 seconds -1 That's it, 5 x 10 5 M -1 seconds -1 That's it, 10 6 M -1 seconds -1 or more or 5 x 10 6 M -1 seconds -1 More than or equal to 10 7 M -1 seconds -1 The IL-33 fragment or variant thereof may bind to redIL-33 with an on-rate (k(on)) of 10 or greater. Preferably, the k(on) rate is 10 or greater. 7 M-1 seconds -1 Preferably, the binding molecules are 5×10 -1 seconds -1 Below, 10 -1 seconds -1 Below, 5 x 10 -2 seconds -1 Below, 10 -2 seconds -1 Below, 5 x 10 -3 seconds -1 Less than or equal to 10 -3 seconds -1 For example, a binding molecule of the present disclosure may specifically bind to redIL-33 with an off rate (k(off)) of 5×10 -4 seconds -1 Below, 10 -4 seconds -1 Below, 5 x 10 -5 seconds -1 Less than or equal to 10 -5 seconds -1 Below, 5 x 10 -6 seconds -1 Below, 10 -6 seconds -1 Below, 5 x 10 -7 seconds -1 Below or 10 -7 seconds -1 It can be said to bind to redIL-33 or a fragment or variant thereof with an off rate (k(off)) of 10 or less. Suitably, the k(off) rate is 10 -3 seconds -1IL-33 is an alarmin cytokine that is released rapidly and at high concentrations in response to inflammatory stimuli. Red IL-33 is converted to its oxidized form approximately 5 to 45 minutes after release into the extracellular environment (Cohen et al., Nat. Commun. 6, 8327 (2015)). Without wishing to be bound by theory, binding to red IL-33 at these k(on) and / or k(off) rates may minimize exposure to red IL-33 prior to conversion from its reduced form to oxIL-33. Furthermore, the k(off) rate may prevent release of IL-33 from the binding molecule / antigen complex prior to in vivo complex disassembly. These binding kinetics may also prevent conversion of red IL-33 to oxIL-33 and thus prevent pathological signaling of the oxidized form of IL-33 via RAGE (as described in WO 2016 / 156440, incorporated herein by reference).

[0275] Suitably, the IL-33 binding molecule is capable of competitively inhibiting the binding of IL-33 to any of the binding molecules recited in Table 6.

[0276] [Table 7]

[0277] [Table 8]

[0278] [Table 9]

[0279] [Table 10]

[0280] [Table 11]

[0281] [Table 12]

[0282] All of these binding molecules are reported to bind to IL-33 and inhibit or attenuate ST-2 signaling. Thus, a binding molecule or binding fragment thereof that competes with any of the antibodies listed in Table 6 for binding to IL-33 may inhibit or attenuate ST-2 signaling.

[0283] A binding molecule or fragment thereof is considered to competitively inhibit the binding of a reference antibody to a given epitope if it specifically binds to that epitope to the extent that it blocks the binding of the reference antibody to that epitope to some extent. Competitive inhibition can be determined by any method known in the art, such as solid-phase assays such as competitive ELISA assays, dissociation-enhanced lanthanide fluorescence immunoassays (DELFIA®, Perkin Elmer), and radioligand binding assays. For example, one skilled in the art can determine whether a binding molecule or fragment thereof competes for binding to IL-33 by using an in vitro competitive binding assay, such as the HTRF assay described in paragraphs 881-886 of WO 2016 / 156440 (incorporated herein by reference). For example, one skilled in the art can label a recombinant antibody from Table 6 with a donor fluorophore and mix multiple concentrations with a fixed concentration sample of redIL-33 labeled with an acceptor fluorophore. Fluorescence resonance energy transfer between the donor and acceptor fluorophores in each sample can then be measured to confirm binding properties. To identify competitive binding molecules, one skilled in the art can first mix various concentrations of test binding molecules with a fixed concentration of labeled antibody from Table 6. A reduction in FRET signal when the mixture is incubated with labeled IL-33 compared to a positive control of labeled antibody only indicates competitive binding to IL-33. A binding molecule or fragment thereof can be said to competitively inhibit binding of a reference antibody to a given epitope by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

[0284] Preferably, the IL-33-binding molecule can be an antibody or antigen-binding fragment comprising the complementarity-determining regions (CDRs) of a pair of variable heavy (VH) and variable light (VL) domains selected from Table 6. Among these, pair 1 corresponds to the VH and VL domain sequences of 33_640087-7B described in WO 2016 / 156440. Pairs 2-7 correspond to the VH and VL domain sequences of antibodies described in U.S. Patent Application Publication No. 2014 / 0271658. Pairs 8-12 correspond to the VH and VL domain sequences of antibodies described in U.S. Patent Application Publication No. 2017 / 0283494. Pair 13 corresponds to the VH and VL domain sequences of ANB020 described in WO 2015 / 106080. Pairs 14-16 correspond to the VH and VL domain sequences of antibodies described in WO 2018 / 081075, Pair 17 corresponds to the VH and VL domain sequences of IL33-158 described in U.S. Patent Application Publication No. 2018 / 0037644, and Pair 18 corresponds to the VH and VL domain sequences of 10C12.38.H6.87Y.581 IgG4 described in WO 2016 / 077381.

[0285] Suitably, the IL-33 binding molecule may competitively inhibit the binding of IL-33 to binding molecule 33_640087-7B (described in WO 2016 / 156440). Suitably, WO 2016 / 156440 discloses that 33_640087-7B binds to redIL-33 with particularly high affinity and attenuates both ST-2- and RAGE-dependent IL-33 signalling.

[0286] Preferably, the IL-33 binding molecule is an anti-IL-33 antibody or antigen-binding fragment thereof comprising a heavy chain variable region (HCVR) complementarity determining region (CDR) comprising the sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) complementarity determining region (CDR) comprising the sequence of SEQ ID NO: 19. These CDRs correspond to those derived from 33_640087-7B (described in WO 2016 / 156440), which binds to reduced IL-33 and inhibits its conversion to oxidized IL-33. 33_640087-7B is described in detail in WO 2016 / 156440, which is incorporated herein by reference. Accordingly, this antibody may be particularly useful in the methods described herein for inhibiting or attenuating both ST-2 and RAGE signaling.

[0287] Preferably, those skilled in the art are familiar with available methods for identifying CDRs within the heavy and light chain variable regions of antibodies or antigen-binding fragments thereof. Preferably, those skilled in the art can perform, for example, sequence-based annotation. Because the regions between CDRs are generally highly conserved, logical rules can be used to determine the locations of CDRs. Those skilled in the art can use a set of sequence-based rules for conventional antibodies (Pantazes and Maranas, Protein Engineering, Design and Selection, 2010). Alternatively, or in addition, those skilled in the art can refine the rules based on multiple sequence alignments. Alternatively, those skilled in the art can use the BLASTP command in BLAST+ to compare antibody sequences with public databases operating using the Kabat, Chothia, or IMGT methods to identify the most closely related annotated sequences. Each of these methods devise a unique residue numbering scheme by numbering the residues in the hypervariable regions and then determining the beginning and end of each of the six CDRs according to specific key positions. For example, CDRs can be extrapolated from an annotated sequence to an unannotated sequence upon alignment with the closest annotated sequence, thereby identifying the CDRs. Suitable tools / databases include, for example, the Kabat database, Kabatman, Scalinger, IMGT, and Abnum.

[0288] Preferably, the binding molecule is an IL-33 antibody or antigen-binding fragment comprising a pair of variable heavy domain (VH) and variable light domain (VL) selected from Table 6.

[0289] Thus, suitably, the IL33 antibody or antigen-binding fragment comprises a VH domain of sequence SEQ ID NO: 1 and a VL domain of sequence SEQ ID NO: 19.

[0290] Thus, suitably, the IL33 antibody or antigen-binding fragment comprises a VH domain of sequence SEQ ID NO: 7 and a VL domain of sequence SEQ ID NO: 25.

[0291] Thus, suitably, the IL33 antibody or antigen-binding fragment comprises a VH domain of sequence SEQ ID NO: 11 and a VL domain of sequence SEQ ID NO: 29.

[0292] Thus, suitably, the IL33 antibody or antigen-binding fragment comprises a VH domain of sequence SEQ ID NO: 13 and a VL domain of sequence SEQ ID NO: 31.

[0293] Thus, suitably, the IL33 antibody or antigen-binding fragment comprises a VH domain of sequence SEQ ID NO: 16 and a VL domain of sequence SEQ ID NO: 34.

[0294] Thus, suitably, the IL33 antibody or antigen-binding fragment comprises a VH domain of sequence SEQ ID NO: 17 and a VL domain of sequence SEQ ID NO: 35.

[0295] Thus, suitably, the IL33 antibody or antigen-binding fragment comprises a VH domain of sequence SEQ ID NO: 18 and a VL domain of sequence SEQ ID NO: 36.

[0296] Preferably, the IL-33 antibody or antigen-binding fragment comprises a variable heavy chain comprising three CDRs derived from a heavy chain variable region independently selected from SEQ ID NOs: 1, 7, 11, 13, 16, 17, and 18.

[0297] Preferably, the IL-33 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the three CDRs of the heavy chain variable region according to SEQ ID NO:1.

[0298] Preferably, the IL-33 antibody or antigen-binding fragment comprises a light chain variable region comprising three CDRs in the light chain variable region independently selected from SEQ ID NOs: 19, 25, 29, 31, 34, 35, and 36.

[0299] Preferably, the IL-33 antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the three CDRs of the light chain variable region according to SEQ ID NO:19.

[0300] Thus, preferably, the IL-33 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising three CDRs of a heavy chain variable region independently selected from SEQ ID NOs: 1, 7, 11, 13, 16, 17, and 18, and a light chain variable region comprising three CDRs of a light chain variable region independently selected from SEQ ID NOs: 19, 25, 29, 31, 34, 35, and 36.

[0301] Thus, preferably, the IL-33 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the three CDRs of the heavy chain variable region according to SEQ ID NO: 1, and a light chain variable region comprising the three CDRs of the light chain variable region according to SEQ ID NO: 19.

[0302] Preferably, the IL-33 antibody or antigen-binding fragment thereof comprises a variable heavy domain (VH) and a variable light domain (VL) having VH CDRs 1-3 having the sequences of SEQ ID NOs: 37, 38, and 39, respectively, wherein one or more VH CDRs have no more than three single amino acid substitutions, insertions, and / or deletions.

[0303] Preferably, the IL-33 antibody or antigen-binding fragment thereof comprises a VH domain comprising VHCDRs 1 to 3 of SEQ ID NO: 37, SEQ ID NO: 38, and SEQ ID NO: 39, respectively.

[0304] Preferably, the IL-33 antibody or antigen-binding fragment thereof comprises a VH domain comprising VHCDRs 1 to 3 consisting of SEQ ID NO: 37, SEQ ID NO: 38, and SEQ ID NO: 39, respectively.

[0305] Preferably, the IL-33 antibody or antigen-binding fragment thereof comprises a variable heavy domain (VH) and a variable light domain (VL) having VL CDRs 1-3 having the sequences of SEQ ID NOs: 40, 41, and 42, respectively, wherein one or more VL CDRs have no more than three single amino acid substitutions, insertions, and / or deletions.

[0306] Preferably, the IL-33 antibody or antigen-binding fragment thereof comprises a VL domain comprising VLCDRs 1 to 3 of SEQ ID NO: 40, SEQ ID NO: 41 and SEQ ID NO: 42, respectively.

[0307] Preferably, the IL-33 antibody or antigen-binding fragment thereof comprises a VL domain comprising VLCDR1 to 3 consisting of SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42, respectively.

[0308] Thus, preferably, the IL-33 antibody or antigen-binding fragment thereof comprises a VHCDR1 having the sequence of SEQ ID NO: 37, a VHCDR2 having the sequence of SEQ ID NO: 38, a VHCDR3 having the sequence of SEQ ID NO: 39, a VLCDR1 having the sequence of SEQ ID NO: 40, a VLCDR2 having the sequence of SEQ ID NO: 41, and a VLCDR3 having the sequence of SEQ ID NO: 42.

[0309] Preferably, the IL-33 antibody or antigen-binding fragment thereof comprises a VH and a VL, wherein the VH has an amino acid sequence at least 90%, e.g., 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100%, identical to a VH according to SEQ ID NOs: 1, 7, 11, 13, 16, 17 and 18.

[0310] Suitably, the IL-33 antibody or antigen-binding fragment thereof comprises a VH and a VL, wherein the VH has an amino acid sequence that is at least 90%, such as 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100%, identical to the VH according to SEQ ID NO:1.

[0311] Preferably, the IL-33 antibody or antigen-binding fragment thereof comprises a VH and a VL, wherein the VH disclosed above has a sequence in which 1, 2, 3, or 4 framework amino acids have been deleted, inserted, and / or independently substituted with different amino acids.

[0312] Suitably, the IL-33 antibody or antigen-binding fragment thereof comprises a VH and a VL, wherein the VL has an amino acid sequence at least 90%, e.g., 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100%, identical to a VL according to SEQ ID NOs: 19, 25, 29, 31, 34, 35 and 36.

[0313] Suitably, the IL-33 antibody or antigen-binding fragment thereof comprises a VH and a VL, wherein the VL has an amino acid sequence at least 90%, such as 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100%, identical to the VL according to SEQ ID NO:19.

[0314] Preferably, the IL-33 antibody or antigen-binding fragment thereof comprises a VH and a VL, wherein the VL has a sequence as disclosed above in which 1, 2, 3, or 4 framework amino acids have been independently deleted, inserted, and / or replaced with different amino acids.

[0315] Suitably, the IL-33 antibody or antigen-binding fragment thereof comprises a VH and a VL, wherein the VH has an amino acid sequence at least 90%, e.g., 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100%, identical to a VH according to SEQ ID NOs: 1, 7, 11, 13, 16, 17 and 18, and the VL has an amino acid sequence at least 90%, e.g., 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identical to a VL according to SEQ ID NOs: 19, 25, 29, 31, 34, 35 and 36.

[0316] Preferably, the IL-33 antibody or antigen-binding fragment thereof comprises a VH and a VL, wherein the VH has the amino acid sequence of SEQ ID NOs: 1, 7, 11, 13, 16, 17, and 18, and the VL has the amino acid sequence of SEQ ID NOs: 19, 25, 29, 31, 34, 35, and 36.

[0317] Preferably, the IL-33 antibody or antigen-binding fragment thereof comprises a VH and a VL, wherein the VH has the amino acid sequence of SEQ ID NO:1 and the VL has the amino acid sequence of SEQ ID NO:19.

[0318] kit In some examples, provided herein are kits for practicing the methods of the disclosure, e.g., for determining the genotype of a polymorphism described herein. In some examples, provided herein are kits for determining whether a patient is at increased risk for an IL-33-mediated disorder. In some examples, provided herein are kits for determining whether a patient suffering from an IL-33-mediated disorder is likely to respond to a treatment comprising an IL-33 axis-binding antagonist. For example, the kit includes first and second oligonucleotides specific for any of the polymorphic regions of IL33 identified above as falling within cluster 1, 2, 3, or 4. The kit may include a plurality of first and second oligonucleotides specific for a corresponding plurality of cluster 1, 2, 3, or 4 polymorphisms. The plurality of cluster 1, 2, 3, or 4 polymorphisms may be any of those identified by the methods described above.

[0319] An oligonucleotide "specific" for a locus binds to or adjacent to a polymorphic region of that locus. For oligonucleotides used as primers for amplification, the primer is adjacent if it is close enough to be used to generate a polynucleotide containing the polymorphic region. In one embodiment, an oligonucleotide is adjacent if it binds within about 1-2 kb of the polymorphism, e.g., less than 1 kb. A specific oligonucleotide can hybridize to a sequence and, under appropriate conditions, will not bind to a sequence that differs by a single base.

[0320] The oligonucleotides included in the kit, whether used as probes or primers, can be detectably labeled. The label can be detected directly (e.g., for fluorescent labels) or indirectly. Indirect detection can include any detection method known to those skilled in the art, including biotin-avidin interactions, antibody binding, etc. Fluorescently labeled oligonucleotides can also include a quenching molecule. The oligonucleotides can be bound to a surface. In some embodiments, the surface is silica or glass. In some embodiments, the surface is a metal electrode.

[0321] Still other kits include at least one reagent necessary for performing an assay. For example, the kit may include an enzyme. Alternatively, the kit may include a buffer or any other necessary reagent. The kit may include all or some of the positive controls, negative controls, reagents, primers, sequencing markers, and probes for determining the patient's genotype.

[0322] composition Also provided herein are compositions comprising any of the IL33 axis binding antagonists disclosed herein for use in any of the examples of the methods disclosed herein. Also provided is the use of any of the above-described IL33 axis binding antagonists in the manufacture of a medicament for use in treating a subject suffering from an IL-33-mediated disorder, wherein the subject's genotype has been determined to include any of the cluster 1, 2, or 3 allele polymorphisms associated with an increased risk of having the IL33-mediated disorder to be treated, or any equivalent allele in a polymorphism in linkage disequilibrium therewith.

[0323] Genetic variants in IL33 have been reported to be associated with asthma and blood eosinophil levels. In this example, IL33 (and IL1RL1) variants are also shown to be associated with age of onset, regardless of eosinophil status, through a study of a large genomic cohort. The effects of predicted rare loss-of-function protein truncation variants (PTVs) (rare splice variants at IL33-rs146597587) and several more common risk variants were investigated. The data also showed that, based on a genetic risk score for common variants in IL33 and IL1RL1, the observed risk reduction for IL33 rare loss-of-function variants was greater in subjects with higher IL33 pathway activity, indicating that a subset of asthma patients suffers from IL33-driven disease, which can be rescued by blocking IL33 activity.

[0324] Human genetic data were generated from the UK Biobank (UKB) project and the FinnGene cohort. This study accessed whole-exome sequencing data for 20,479 asthma patients and 109,902 respiratory control subjects, as well as 64,773 asthma patients and 353,516 control subjects genotyped within UKB. Asthma subjects were identified by combining self-reported asthma cases and subjects with recorded asthma hospitalizations. Age at onset was captured by self-report and physician-diagnosed age. Association of common variants at the IL33 and IL1RL1 loci with asthma was assessed using UKB GWAS results. [Example]

[0325] Example 1 The following examples are offered by way of illustration and not by way of limitation.

[0326] Subjects with a high genetic risk score in the IL33 pathway show greater benefit from carrying rare loss-of-function variants in IL33 To define a genetic risk score for IL-33-induced asthma, we collected 222 common variants in IL33 reported to affect IL33 expression levels (obtained from GTEx_Portal (January 16, 2020)) and 774 variants reported to affect IL1RL1 mRNA or protein levels or result in changes in the IL1RL1 amino acid sequence (obtained from GTEx Portal (January 16, 2020); Sun et al., Nature. 2018 Jun;558(7708):73-79; Gotenboer et al., J Allergy Clin Immunol. 2013 Mar;131(3):856-65; Ho et al., J Clin Invest. 2013 Oct;123(10):4208-18). An elastic net regression model for asthma was used to fit the UKB data. Of the 996 variants, 43 were selected as informative by the model. This means that they had non-zero coefficients.The common variant genetic risk score for IL33-induced asthma was then obtained as the weighted sum of the genotype counts for these 43 variants in all UKB subjects.The score was scaled to range from zero (i.e., the lowest common variant risk) to 1 (i.e., the highest common variant risk).

[0327] Comparing UKB subjects with the lowest (gene score = 0) and highest (gene score = 1) risk of IL-33-induced asthma, we found a more than two-fold difference in asthma risk (OR 2.19, CI 2.05-2.34, p: 1.03 × 10-114) (Figure 1). Logistic regression of the effect of IL33 loss-of-function variant rs146597587 carriage status on asthma risk revealed a statistically significant interaction coefficient with the common variant gene risk score of 0.36 (CI 0.16-0.83, p 0.016), indicating that the protective effect of the loss-of-function variant was stronger with higher common variant risk scores. This effect seen in the overall logistic regression of the common variant score and its interaction with loss-of-function alleles can be visualized by comparing the effect of loss-of-function alleles within the extreme deciles of the common variant score (i.e., lowest-risk vs. highest-risk subgroup comparison) (Figure 2).

[0328] As a negative control, we performed a similar logistic regression between carrier status and the elastic net risk score generated for three unrelated asthma disease genes (ORMDL3, ADAM33, and TSLP), but found no statistically significant association (p: 0.263) (Figure 3). This indicates that the rescue effect observed for carrier status of rs146597587 when applied to the IL33 risk score is not generally associated with any asthma risk score.

[0329] Rare loss-of-function IL33 variants reduce the risk of early-onset asthma To identify associations between rare variants in IL33 and asthma-related phenotypic traits acquired in the UKB cohort, we performed an exome-wide association study (exWAS). A case / control association study was performed by combining self-reported asthma cases with subjects with hospitalized episodes of asthma and contrasting them with a cohort of respiratory controls (subjects without reported respiratory pathology).

[0330] The variant rs146597587 was found to have a significant protective effect against asthma (OR = 0.59, 95% CI 0.47-0.73, p 2.1 × 10 -7 , MAF=0.4%) (Figure 4). We also found that this variant was less common in patients with early-onset (<18 years) asthma, as opposed to those with late-onset (≥18 years) asthma, with an OR of 0.49 (p=0.015).

[0331] These observations indicate that IL33 is an important factor in asthma, especially in patients with early onset of the disease.

[0332] A set of common variants at the IL33 locus is associated with both asthma risk and early onset of asthma To characterize previously reported asthma risk variants at the IL33 locus, we conducted a database search within the GWAS catalog (Buniello et al., Nucleic Acids Res. 2019 Jan 8;47(D1):D1005-D1012). This identified 39 common variants at the IL33 locus associated with asthma, other respiratory disorders, or eosinophil levels. Our analysis of the UKB cohort confirmed the positive association of 32 of these SNPs with asthma risk (Table 7). However, the UKB genotype data revealed novel associations with age at asthma onset (Table 8) (64,773 of 487,409 subjects had asthma and 353,516 were respiratory controls).

[0333] Linkage disequilibrium (i.e., allelic correlation) analysis of the 39 variants revealed four major clusters, with variants in clusters 1, 2, and 3 showing high inter-cluster correlation (Figure 5). Although no variants were present in the IL33 protein-coding region, many of the variants were found in close proximity to known transcription factor binding sites, as identified by ChIP-seq experiments in ENCODE (Figure 6). All variants in clusters 1, 2, and 3 (Figure 7) showed a strong association with asthma and age at asthma onset (Figure 7). We also performed an onset analysis adjusted for eosinophil count by adding eosinophil count as a covariate in linear regression. This allowed us to analyze the impact of variants on asthma onset while controlling for the influence of eosinophils. The significant association with onset remained even when accounting for the influence of eosinophils, suggesting that IL33 acts on asthma onset through an eosinophil-independent pathway.

[0334] To elucidate the potential functional mechanisms underlying the asthma association, we performed a colocalization analysis using coloc (Plagnol et al., Biostatistics. 2009 Apr;10(2):327-34) between the asthma-associated peaks at the IL33 locus in UKB and the IL33 eQTL data from aortic tissue obtained from GTEx(v8). A common issue when comparing two association peaks at the same locus (in this case, the association between asthma and IL-33 gene expression) is whether the same or different causal variants are tagged by the associated variants. We performed statistical analysis using the R package coloc to estimate the probability that the same causal variant is involved in both signals. We found a high probability of colocalization (i.e., the same underlying causal variant) of P = 0.976 (coloc post hoc for shared causal variants) (Table 7). Looking at the consistent direction of effect on asthma and IL-33 expression, we observe that for the 39 variants in the candidate set, alleles that increase asthma risk always also increase IL-33 expression, and vice versa (Table 8).

[0335] To further characterize the interaction between variant effects on IL-33 expression and asthma, we selected the eQTL variant (rs928413) with the greatest effect on IL-33 expression in GTEx for further analysis. The risk allele of rs928413 (G) was associated with increased asthma risk (OR 1.14, p-value 2.91 × 10-61) and a lower age at onset (effect size beta = -1.22, p-value 9.7 × 10-24) in the UK Biobank cohort (Figure 8).

[0336] Taken together, our analysis of common variants at the IL-33 locus within the UK Biobank confirms IL33 as an asthma susceptibility gene. We also show that IL33 variants are associated with the development of asthma in an eosinophil-independent manner and identify altered gene expression as a possible functional mechanism for these variants. Finally, we present data supporting the increased protective effect of IL33 loss-of-function variants in subjects with increased IL33 pathway activity due to a common variant genetic background.

[0337] [Table 13]

[0338] [Table 14]

[0339] [Table 15]

[0340] [Table 16]

[0341] method Selection and clustering analysis of asthma-associated variants in the IL33 locus A database search in the EBI GWAS catalogue for asthma (https: / / www.ebi.ac.uk / gwas / ), combined with searches within previous publications, identified 39 common variants within the IL33 locus associated with asthma, other respiratory disorders, or eosinophil levels.

[0342] Asthma associations in the UK Biobank Statistical analyses were performed on the UK Biobank cohort. 64,773 asthma cases were identified by combining subjects with self-reported diagnoses or records of hospitalization due to asthma. 353,516 controls were selected based on the absence of any lung disease / pulmonary dysfunction in electronic health records. Age at onset of asthma was analyzed as a quantitative trait or as a binary variable of "early onset" / "late onset" with a cutoff age of 18 years. SNP clustering was performed based on Pearson correlation of the number of risk alleles of each SNP in asthmatic subjects. Association with asthma was performed using logistic regression, and association with age at onset of asthma was performed using linear regression in R (version 3.5.3). Age, sex, and the first 10 UK Biobank principal components (controls for population stratification) were adjusted as cofactors. Odds ratios were calculated. P values ​​were adjusted for multiple comparisons using the Bonferroni method.

[0343] Colocalization analysis of the association between asthma and IL33 eQTL Colocalization analysis of asthma-related peaks and IL33 eQTL signals in GTEx(v8) aortic tissue was performed using the R package coloc (version 3.2-1, https: / / cran.r-project.org / web / packages / coloc / index.html). Summary statistics of GTEx eQTL effects are publicly available on gtexportal.org.

[0344] Common variant genetic risk for IL-33-induced asthma To define a common-variant genetic risk score for IL-33-induced asthma, we identified genetic variants in the IL-33 and IL1RL1 loci using prior evidence for the functional relevance of each gene. This included 222 variants in the IL-33 locus that have been reported to affect IL-33 expression in GTEx and 774 variants that affect either IL1RL1 expression (GTEx), protein level (Sun et al., Nature. 2018 Jun;558(7708):73-79), or protein function (Gotenboer et al., J Allergy Clin Immunol. 2013 Mar;131(3):856-65; Ho et al., J Clin Invest. 2013 Oct;123(10):4208-18). To ensure independence between the common variant score and the IL-33 loss-of-function variant rs146597587, SNPs showing any LD (r² > 0.01) with rs146597587 were excluded. Elastic net regression models using these 996 variants as predictors and asthma as the response variable were fitted to the UKB data using the R package glmnet (version 3.0.2). The alpha hyperparameter was set to 0.5. The lambda hyperparameter was fitted using 10-fold cross-validation, and the parameter value that minimized deviance was selected for the final model. Model fitting yielded 43 variants with nonzero coefficients. Using these weights, a common variant genetic risk score for IL-33-induced asthma was then obtained as a simple weighted sum of the genotype counts for these 43 variants across all UKB subjects. The score was scaled to range from zero (i.e., lowest common variant risk) to 1 (i.e., highest common variant risk).To test for interactions between the common variant genetic risk score and the protective effect of the IL33 loss-of-function rare variant rs146597587, we performed logistic regression using the common variant risk score and rs146597587 carrier status as predictors and asthma as the response. By including an interaction term for the common variant risk score and rs146597587 carrier status, we were able to test for differential effects of loss-of-function variants on the common variant genetic background.

[0345] Example 2 Functional significance of variants in causing the IL-33 phenotype The functional significance of asthma-associated IL33 SNP variants was assessed in vitro using a dual-luciferase reporter assay in which luciferase expression was driven by the IL33 promoter. A 3-kb segment containing either the wild-type (WT) sequence or a sequence containing a single SNP variant, derived from the 5'-upstream intergenic or promoter region of IL33, was cloned upstream of the IL33 promoter in the IL33-NanoLuc reporter construct. Meanwhile, a 1.5-kb segment containing either the WT sequence or an intronic SNP was cloned downstream of the NanoLuc gene in the IL33-NanoLuc reporter construct. These constructs were then used to determine how the variants affected IL33 promoter activity under basal, low-cytokine, and high-cytokine conditions. Increased luciferase activity under various conditions correlated with enhanced IL33 promoter activity.

[0346] Briefly, A549 cells were transfected with WT and SNP-containing constructs and subsequently treated with a low-concentration cytokine mixture (2.5 ng / mL TNF-alpha + 12.5 ng / mL IFN-gamma), a high-concentration cytokine mixture (10 ng / mL TNF-alpha + 50 ng / mL IFN-gamma), or medium control (basal conditions). To quantify the effect of SNPs on IL-33 promoter activity, transiently transfected A549 cells were lysed, and the luciferase activities of NanoLuc and Firefly were measured 26–27 h after transfection. Using a dual-luciferase assay, 70 SNP-containing constructs were screened. SNPs were associated with increased asthma risk. The corresponding WT sequence construct was included on each plate as a control. The effects of SNPs were normalized to percent activity compared to the normalized NanoLuc luciferase activity from the WT sequence construct control on the plate (set at 0% activity). This screen identified 13 SNPs in the 5'-upstream intergenic and promoter regions of IL33 and one SNP in intron-1 as conferring significant enhancement of NanoLuc luciferase activity under basal or low- or high-concentration cytokine treatment (Table 9). All of these hits were run two to four times with n = 3 per run. Surprisingly, the results show that two SNPs in segment 11 (rs1475658_T and rs13298116_T) exhibited a strong enhancing effect on IL33 promoter activity under basal conditions. This effect was not necessarily segment-specific, as rs1929995_C in segment 11 did not induce any increase in NanoLuc luciferase activity under basal or cytokine-stimulated conditions (Figure 9).

[0347] [Table 17]

[0348] Interestingly, other SNP hits showed potentiating effects under cytokine-stimulated conditions (Table 9). For example, three SNPs in segment 13 (rs144829310_T, rs7046661_C, and rs992969_A) showed significant potentiation under high-concentration cytokine treatment (Figure 10). The mechanisms by which these SNPs regulate IL33 promoter activity are unclear and require further investigation.

[0349] These observations were corroborated by ex vivo analysis of IL-33 expression levels in nasal scrapes from the U-BIOPRED cohort (N=75). The association between the active inducing alleles in the luciferase assay of the 14 SNPs in Table 9 and IL-33 gene expression was tested using linear regression. Nominally significant increased expression (beta > 0.0, P < 0.05) was observed for the luciferase inducing alleles of 11 of the 14 SNPs (Table 9, Figure 12). This analysis provides further evidence that the SNPs identified in the luciferase assay play a direct role in regulating IL-33.

[0350] These results identify for the first time which IL33 SNPs may contribute to the pathogenesis of IL-33-mediated disorders by increasing IL-33 expression. Therefore, subjects with these SNPs may be particularly amenable to treatment with anti-IL-33-based therapies. Therefore, identifying these SNPs in subjects suffering from conditions such as asthma provides a precision medicine approach to identify subjects most likely to respond to IL-33-based therapies.

[0351] method cell line The A549 human adenocarcinoma alveolar basal epithelial cell line was obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA). Cells were cultured in phenol red-free DMEM medium (31053028, ThermoFisher Scientific, Waltham, MA, USA) supplemented with 10% fetal bovine serum (10270106, ThermoFisher Scientific), 1 mM sodium pyruvate (11360070, ThermoFisher Scientific), and 2 mM Glutamax-I (35050038, ThermoFisher Scientific).

[0352] Luciferase reporter constructs The human IL33 promoter region was amplified by PCR using genomic DNA isolated from A549 cells. The IL33 promoter was cloned into the pNL1.2[NlucP] luciferase reporter vector (N1011, Promega Biotech, Nacka, Sweden) to create the IL33-NanoLuc reporter vector. Fourteen slid 3-kb segments upstream of the IL33 promoter were PCR-amplified using genomic DNA isolated from A549 cells and subcloned into the IL33-NanoLuc reporter vector, one 3-kb segment per vector, upstream of the IL33 promoter. The size of the IL33-NanoLuc reporter vector containing one 3-kb segment is approximately 8.8 kb. SNP variants in the 3-kb segments and the IL33 promoter were generated by PCR-based site-directed mutagenesis and verified by Sanger sequencing. The segment containing the intronic SNP was synthesized as two adjacent 750 bp fragments, which were then assembled into a single 1.5 kb segment (using the NEBuilder HiFI DNA standard protocol). The 1.5 kb segment was cloned downstream of the NanoLuc gene in the IL33-NanoLuc reporter vector between the XbaI and FseI sites.

[0353] A549 transfection and luciferase reporter assay A549 cells were transfected using Fugene HD Transfection Reagent (Promega Biotech) at a plasmid DNA:transfection reagent ratio of 3. Briefly, 12,000 cells per well in 90 μL were seeded into a 96-well plate 24 h prior to transfection and transfected with 98 ng of test IL33-NanoLuc reporter plasmid DNA and 2 ng of normalization Firefly control plasmid pGL4.53[luc2 / PGK] (E5011, Promega Biotech). After 3–4 h, cells were stimulated with different concentrations of a combination mixture of TNF-alpha (210-TA, R&D Systems, Minneapolis, MN, USA) and IFN-gamma (285-IF, R&D Systems) or medium alone (basal control). NanoLuc and Firefly luciferase activities were measured 26–27 h after transfection using the Nano-Glo Dual-Luciferase Reporter Assay Kit (N1630, Promega Biotech) according to the manufacturer's protocol. NanoLuc luciferase activity was normalized to Firefly luciferase activity to account for variations in cell transfection and lysis efficiency.

[0354] UBIOPRED IL-33 expression analysis The U-BIOPRED (Unbiased Biomarkers for Predicting Outcomes in Respiratory Diseases) cohort includes samples from nasal scrapes of 75 subjects. IL-33 expression in these samples was measured by RNA microarray. Genotypes of 14 variants (Table 9) for the tested subjects were extracted from U-BIOPRED whole-genome sequencing performed at the AstraZeneca Centre for Genomics Research. The effect of active inducible alleles from the luciferase assay on IL-33 expression was assessed by linear regression using age and sex as covariates.

[0355] Additional arrays SEQ ID NO: 37: SYAMS SEQ ID NO: 38: GISAIDQSTYYADSVKG SEQ ID NO: 39: QKFMQLWGGGLRYPFGY SEQ ID NO: 40: SGEGMGDKYAA SEQ ID NO: 41: RDTKRPS SEQ ID NO: 42: GVIQDNTGV SEQ ID NO: 43: (wherein n is g) tagttagcta ctttttaata gttacnagag cattggccaa ggcagggaat c 51 SEQ ID NO: 44: (n is t) atgcagaaca acaatgtgtt ttccangtgc acttggtcaa cacctatatc t 51 SEQ ID NO: 45: (n is a) ttcctcggac tggaccattt caattnacct atcactggtt cttgcttctg a 51 SEQ ID NO: 46: (n is t) tccacatccc catggtttgt tgttgntgct tgtagtgggt tgttgttatc t 51 SEQ ID NO: 47: (n is c) atggaggaaa gaaacaatgg acttanaagt caatagaaat tatctgattt g 51 SEQ ID NO: 48: (n is a) tatgattcag ataacaaatt atacgnttac tagaataaag tctgtatgac c 51 SEQ ID NO: 49: (n is t) aggagacaga gaaatcactg ttgatnggtg ttgtgggaat gaagagacaa a 51 SEQ ID NO: 50: (n is t) attaaaatgt caggaaacaa cagatnctgg agaggatgtg gagaaatagg a 51 SEQ ID NO: 51: (n is t) ggaagaagaa tgcatcaact gaaaanctat tcctttgaga ggaccaataa a 51 SEQ ID NO: 42: (n is g) taattaaaat cactgatgca gaacancaat gtgttttcca tgtgcacttg g 51 SEQ ID NO: 53: (n is c) ctctagagag acagaactaa tagaanagat atataaagga gtttagtagg t 51 SEQ ID NO: 54: (n is g) ccctataaga attctgcatc catccntggt aaaaagtcac tctgcaggag c 51 SEQ ID NO: 55: (n is c) atataaataa gaataagagg tcatgntggt gtcttcatga gaaaagattg g 51 SEQ ID NO: 56: (n is t) aaactcctga aacagcagaa agaaanggac cttaattcta tcaacaacaa a 51 SEQ ID NO: 57: (n is g) tgtaatccca gcactttggg aggccnaggg gggcagatca cgaggtcagg a 51 SEQ ID NO: 58: (n is g) agcactttgg gaggccaagg ggggcngatc acgaggtcag gagatcgaga c 51 SEQ ID NO: 59: (n is a) ttcccaccta tgagtgagaa tatgcngtgt ttggtttttt gttcttgcca t 51 SEQ ID NO: 60: (n is t) gctcccacac gttctaatgc atttangtag ctccatctgc attgcctcat a 51 SEQ ID NO: 61: (n is g) gttgtggtat gtatttggaa ggaaanaaaa atcccaaatg tattcttttt t 51 SEQ ID NO: 62: (n is c) atttggtcca gaaaggtggg ataacntgaa gcgtggggtg gaggggttca g 51 SEQ ID NO: 63: (n is t) gtggcattca cattgttgta caaccntaac cactctccat ctccagaaca t 51 SEQ ID NO: 64: (n is g) ctcccacaag gccccacctc caacantggg gatcaaattt caacaggaga c 51 SEQ ID NO: 65: (n is c) caagtgcgtt ctctcaaact agtccntgag ggtgataaga cgggagaaaa a 51 SEQ ID NO: 66: (n is c) ctcattctct cactagttcc tcctcnactg caggaagaag tgtgcctcct c 51 SEQ ID NO: 67: (n is g) atgtgctcaa agtggttggt gtgcantttg gttttatgca ttttagggag a 51 SEQ ID NO: 68: (n is c) tgtgctcaaa gtggttggtg tgcatnttgg ttttatgcat tttagggaga c 51 SEQ ID NO: 69: (n is c) acaggaggcc atacttaaaa agaagnagca ataattattg atagaattgc a 51 SEQ ID NO: 70: (n is c) tttctgttga gacagtctca ctttgnctcc caggctgaag tgcagtggca c 51 SEQ ID NO: 71: (n is t) aggctgcagt gagctgagat cgtgcnactg cactccagcc tgggcagcag a 51 SEQ ID NO: 72: (n is t) ggaaatgaaa tatccagggt gcagantgtg gcttatttta ttcagataaa t 51 SEQ ID NO: 73: (n is a) accaagcttc tgtccccttc tctctncagc cccttcacat tatgctctcc c 51 SEQ ID NO: 74: (n is g) aagtagtttg atttcagact acaaanccat gtaggggctg acttgtcctg a 51 SEQ ID NO: 75: (n is c) gctctggttt ctccccatct ttgtgntttt atctaccttt ggtctttgat g 51 SEQ ID NO: 76: (n is c) gagtaggtca ttacctgata attttngtta ttcaaaacta agtaatattt t 51 SEQ ID NO: 77: (n is a) gggagaggat cagaaaaaat aactantggg tactaggctt aatacctggg t 51 SEQ ID NO: 78: (n is g) ttaaaaatac atcttgcagc attttngttg tttttatcag gagggctgtt c 51 SEQ ID NO: 79: (n is c) gattgctttc tctcttgttt cctcanctcc ataagtgtga aaaaccactg c 51 SEQ ID NO: 80: (n is t) tttcagataa ggtgttactg agttantatg agtctcaaca cccctcaaat g 51 SEQ ID NO: 81: (n is g) ctcagcttcc aaaagtgctg ggactntaag gcttgagcca ccacccccag c 51 SEQ ID NO: 82 (n is c) ttaatttctt aatgtcttac ttactntctc atttttaaag aatagttttt c 51 SEQ ID NO: 83 (n is t) aagctttttc aaagaaataa taacanaaac cttccaaacc tggagaaaga t 51 SEQ ID NO: 84 (n is t) taaggtgtaa ggaagggatc cagttncagc tttctacata tggctagcca g 51 SEQ ID NO: 85 (n is t) acaatagtta tttttccttt tttttnaaaa aaaaattaca tgcatcctag t 51 SEQ ID NO: 86 (n is g) cagaaataaa atcctttaca gacatncaaa tgctgagcga ttttgtcacc t 51 SEQ ID NO: 87 (n is t) cttttggtgt tttagacatg aagtcnttgc ccatgcctat gtcctgaatg g 51 SEQ ID NO: 88 (n is t) caatagttat ttttcctttt tttttnaaaa aaaattacat gcatcctagt g 51

Claims

1. 1. A method for treating a patient suffering from asthma, comprising administering to said patient an IL-33 axis binding antagonist, wherein said patient's genotype has been determined to include at least one allele of a Cluster 2 polymorphism as defined in Table 1, or an equivalent allele at a polymorphism in linkage disequilibrium therewith.

2. 1. A method for determining whether a patient suffering from asthma is likely to respond to a therapy comprising an IL-33 axis binding antagonist, the method comprising: (a) determining, in a sample from the patient, the genotype of at least one Cluster 2 polymorphism as defined in Table 1 or an equivalent allele of a polymorphism in linkage disequilibrium therewith; and (b) identifying the patient as likely to respond to a therapy comprising an IL-33 axis binding antagonist based on the genotype, wherein the presence of at least one allele of a Cluster 2 polymorphism or an equivalent allele of a polymorphism in linkage disequilibrium therewith indicates that the patient has an increased likelihood of responding to a therapy comprising an IL-33 axis binding antagonist.

3. 1. A method for determining whether a patient is at increased risk for asthma, comprising identifying a genotype for at least one Cluster 2 polymorphism as defined in Table 1 or an equivalent allele of a polymorphism in linkage disequilibrium therewith from a sample obtained from the patient, wherein if the patient's genotype comprises at least one Cluster 2 polymorphism as defined in Table 1 or an equivalent allele of a polymorphism in linkage disequilibrium therewith, the patient is at increased risk for an IL-33-mediated disorder.

4. 4. The method of claim 2 or 3, further comprising administering to the patient an IL-33 axis binding antagonist.

5. The method of any one of claims 1 to 4, wherein the IL-33 mediated disorder is early onset asthma.

6. The genotypes of the patient are a G allele at polymorphism rs928413 (SEQ ID NO: 43), a T allele at polymorphism rs1888909 (SEQ ID NO: 44), an A allele at polymorphism rs992969 (SEQ ID NO: 45), a T allele at polymorphism rs3939286 (SEQ ID NO: 46), a C allele at polymorphism rs2381416 (SEQ ID NO: 47), an A allele at polymorphism rs928412 (SEQ ID NO: 48), and a polymorphism rs7848215 (SEQ ID NO: 49). The method according to any one of claims 1 to 5, wherein the polymorphism comprises at least one allele of a polymorphism selected from the group consisting of a T allele at polymorphism rs7046661 (SEQ ID NO: 82), a C allele at polymorphism rs10815363 (SEQ ID NO: 83), a T allele at polymorphism rs62558407 (SEQ ID NO: 84), a T allele at polymorphism rs1475658 (SEQ ID NO: 85), and a G allele at polymorphism rs10975481 (SEQ ID NO: 86).

7. The genotype of the patient was two G alleles at polymorphism rs928413 (SEQ ID NO: 43), two T alleles at polymorphism rs1888909 (SEQ ID NO: 44), two A alleles at polymorphism rs992969 (SEQ ID NO: 45), two T alleles at polymorphism rs3939286 (SEQ ID NO: 46), two C alleles at polymorphism rs2381416 (SEQ ID NO: 47), two A alleles at polymorphism rs928412 (SEQ ID NO: 48), and two A alleles at polymorphism rs7848215 (SEQ ID NO: 49).

7. The method of claim 1, wherein the polymorphism comprises at least two alleles of a polymorphism selected from two T alleles at polymorphism rs7046661 (SEQ ID NO: 82), two C alleles at polymorphism rs10815363 (SEQ ID NO: 83), two T alleles at polymorphism rs62558407 (SEQ ID NO: 84), two T alleles at polymorphism rs1475658 (SEQ ID NO: 85), and two G alleles at polymorphism rs10975481 (SEQ ID NO: 86).

8. The method of any one of claims 1 to 7, wherein the genotype of the patient comprises at least one G allele at polymorphism rs928413 (SEQ ID NO: 43), at least one A allele at polymorphism rs992969 (SEQ ID NO: 45), a C allele at polymorphism rs7046661 (SEQ ID NO: 82), a T allele at polymorphism rs10815363 (SEQ ID NO: 83), a T allele at polymorphism rs62558407 (SEQ ID NO: 84), a T allele at polymorphism rs1475658 (SEQ ID NO: 85), and a G allele at polymorphism rs10975481 (SEQ ID NO: 86).

9. 9. The method of claim 8, wherein the genotype of the patient comprises two G alleles at polymorphism rs928413 (SEQ ID NO: 43), two A alleles at polymorphism rs992969 (SEQ ID NO: 45), two C alleles at polymorphism rs7046661 (SEQ ID NO: 82), two T alleles at polymorphism rs10815363 (SEQ ID NO: 83), two T alleles at polymorphism rs62558407 (SEQ ID NO: 84), two T alleles at polymorphism rs1475658 (SEQ ID NO: 85), and two G alleles at polymorphism rs10975481 (SEQ ID NO: 86).

10. The method of any one of claims 1 to 9, wherein the genotype of the patient comprises one or two T alleles at polymorphism rs1475658 (SEQ ID NO: 85).

11. 11. The method of any one of claims 1 to 10, wherein the genotype of the patient further comprises at least one allele of, or at least one polymorphism in linkage disequilibrium with, at least one Cluster 3 polymorphism as defined in Table 2, and / or the genotype further comprises at least one allele of, or at least one polymorphism in linkage disequilibrium with, at least one Cluster 1 polymorphism as defined in Table 3.

12. 1. A method for treating a patient suffering from asthma, comprising administering to said patient an IL-33 axis binding antagonist, wherein said patient's genotype has been determined to include at least one allele of a Cluster 3 polymorphism as defined in Table 2, or an equivalent allele of a polymorphism in linkage disequilibrium therewith.

13. 1. A method for determining whether a patient suffering from asthma is likely to respond to a therapy comprising an IL-33 axis binding antagonist, the method comprising: (a) determining, in a sample from the patient, the genotype of at least one Cluster 3 polymorphism as defined in Table 2, or an equivalent allele of a polymorphism in linkage disequilibrium therewith; and (b) identifying the patient as likely to respond to a therapy comprising an IL-33 axis binding antagonist based on the genotype, wherein the presence of at least one allele of a Cluster 3 polymorphism, or an equivalent allele of a polymorphism in linkage disequilibrium therewith, indicates that the patient has an increased likelihood of responding to a therapy comprising an IL-33 axis binding antagonist.

14. 1. A method for determining whether a patient is at increased risk for asthma, comprising identifying a genotype for at least one Cluster 3 polymorphism as defined in Table 2 or an equivalent allele of a polymorphism in linkage disequilibrium therewith from a sample obtained from the patient, wherein if the patient's genotype comprises at least one Cluster 3 polymorphism as defined in Table 2 or an equivalent allele of a polymorphism in linkage disequilibrium therewith, the patient is at increased risk for an IL-33-mediated disorder.

15. 15. The method of claim 13 or 14, further comprising administering to the patient an IL-33 axis binding antagonist.

16. The method of any one of claims 12 to 15, wherein the asthma is early onset asthma.

17. The method of any one of claims 12 to 16, wherein the genotype of the patient comprises at least one allele of a polymorphism selected from a T allele at polymorphism rs72699186 (SEQ ID NO: 51), a G allele at polymorphism rs7032572 (SEQ ID NO: 54), a G allele at polymorphism rs7032572 (SEQ ID NO: 54), a T allele at polymorphism rs144829310 (SEQ ID NO: 50), a G allele at polymorphism rs10975488 (SEQ ID NO: 58), a T allele at polymorphism rs552376976 (SEQ ID NO: 87), and a T allele at polymorphism rs13298116 (SEQ ID NO: 88).

18. The method of any one of claims 12 to 17, wherein the genotype of the patient comprises at least two alleles of a polymorphism selected from two T alleles at polymorphism rs72699186 (SEQ ID NO: 51), two G alleles at polymorphism rs7032572 (SEQ ID NO: 54), two G alleles at polymorphism rs7032572 (SEQ ID NO: 54), two T alleles at polymorphism rs144829310 (SEQ ID NO: 50), two G alleles at polymorphism rs10975488 (SEQ ID NO: 58), two G alleles at polymorphism rs10975488 (SEQ ID NO: 58), two T alleles at polymorphism rs552376976 (SEQ ID NO: 87), and two T alleles at polymorphism rs13298116 (SEQ ID NO: 88).

19. The method of any one of claims 12 to 18, wherein the genotype of the patient comprises one or two T alleles at polymorphism rs13298116 (SEQ ID NO: 88).

20. 20. The method of any one of claims 12 to 19, wherein the genotype of the patient further comprises at least one allele of, or at least one polymorphism in linkage disequilibrium with, at least one Cluster 2 polymorphism as defined in Table 1, and / or the genotype further comprises at least one allele of, or at least one polymorphism in linkage disequilibrium with, at least one Cluster 1 polymorphism as defined in Table 3.

21. 1. A method for treating a patient suffering from asthma, comprising administering to said patient an IL-33 axis binding antagonist, wherein said patient's genotype has been determined to include at least one allele of a Cluster 1 polymorphism as defined in Table 3, or an equivalent allele of a polymorphism in linkage disequilibrium therewith.

22. 1. A method for determining whether a patient suffering from asthma is likely to respond to a therapy comprising an IL-33 axis binding antagonist, the method comprising: (a) determining, in a sample from the patient, the genotype of at least one Cluster 1 polymorphism as defined in Table 3, or an equivalent allele of a polymorphism in linkage disequilibrium therewith; and (b) identifying the patient as likely to respond to a therapy comprising an IL-33 axis binding antagonist based on the genotype, wherein the presence of at least one allele of a Cluster 1 polymorphism, or an equivalent allele of a polymorphism in linkage disequilibrium therewith, indicates that the patient has an increased likelihood of responding to a therapy comprising an IL-33 axis binding antagonist.

23. 1. A method for determining whether a patient is at increased risk for asthma, comprising identifying a genotype for at least one Cluster 1 polymorphism as defined in Table 3 or an equivalent allele of a polymorphism in linkage disequilibrium therewith from a sample obtained from the patient, wherein if the patient's genotype comprises at least one Cluster 1 polymorphism as defined in Table 3 or an equivalent allele of a polymorphism in linkage disequilibrium therewith, the patient is at increased risk for an IL-33 mediated disorder.

24. 24. The method of claim 22 or 23, further comprising administering to the patient an IL-33 axis binding antagonist.

25. The method of any one of claims 21 to 24, wherein the asthma is early onset asthma.

26. The genotypes of the patient were a T allele at polymorphism rs10975507 (SEQ ID NO: 60), a G allele at polymorphism rs10975504 (SEQ ID NO: 61), a C allele at polymorphism rs10815393 (SEQ ID NO: 62), a T allele at polymorphism rs12339348 (SEQ ID NO: 63), a G allele at polymorphism rs7035413 (SEQ ID NO: 64), a C allele at polymorphism rs17498196 (SEQ ID NO: 65), a C allele at polymorphism rs17582919 (SEQ ID NO: 66), a G allele at polymorphism rs17498196 (SEQ ID NO: 67), a C allele at polymorphism rs17582919 (SEQ ID NO: 68), a G allele at polymorphism rs17498196 (SEQ ID NO: 69), a C allele at polymorphism rs17582919 (SEQ ID NO: 70), a G allele at polymorphism rs17498196 (SEQ ID NO: 71), a C allele at polymorphism rs17582919 (SEQ ID NO: 72), a G allele at polymorphism rs17498196 (SEQ ID NO: 73), a C allele at polymorphism rs17582919 (SEQ ID NO: 74), a G allele at polymorphism rs17498196 (SEQ ID NO: 75), a C allele at polymorphism rs17582919 (SEQ ID NO: 76), a G allele at polymorphism rs17498196 (SEQ ID NO: 7 26. The method of any one of claims 21 to 25, comprising at least one allele in a polymorphism selected from the group consisting of a C allele in polymorphism rs10815391 (SEQ ID NO: 67), a G allele in polymorphism rs10815392 (SEQ ID NO: 68), a C allele in polymorphism rs72689561 (SEQ ID NO: 69), a C allele in polymorphism rs7038893 (SEQ ID NO: 70), and a T allele in polymorphism rs112935616 (SEQ ID NO: 71).

27. The genotype of the patient was two T alleles at polymorphism rs10975507 (SEQ ID NO: 60), two G alleles at polymorphism rs10975504 (SEQ ID NO: 61), two C alleles at polymorphism rs10815393 (SEQ ID NO: 62), two T alleles at polymorphism rs12339348 (SEQ ID NO: 63), two G alleles at polymorphism rs7035413 (SEQ ID NO: 64), two C alleles at polymorphism rs17498196 (SEQ ID NO: 65), two C alleles at polymorphism rs17582919 (SEQ ID NO: 66), two T alleles at polymorphism rs12339348 (SEQ ID NO: 67), two G alleles at polymorphism rs17498196 (SEQ ID NO: 68), two C alleles at polymorphism rs17582919 (SEQ ID NO: 69), two T alleles at polymorphism rs12339348 (SEQ ID NO: 70), two G alleles at polymorphism rs17498196 (SEQ ID NO: 71), two C alleles at polymorphism rs17582919 (SEQ ID NO: 72), two T alleles at polymorphism rs12339348 (SEQ ID NO: 73), two G alleles at polymorphism rs17498196 (SEQ ID NO: 74), two C alleles at polymorphism rs17582919 (SEQ ID NO: 75), two G alleles at polymorphism rs17498196 (SEQ ID NO: 76), two C alleles at polymorphism 27. The method of any one of claims 21 to 26, wherein the polymorphism comprises two alleles at polymorphisms selected from two C alleles at polymorphism rs10815391 (SEQ ID NO: 67), two G alleles at polymorphism rs10815392 (SEQ ID NO: 68), two C alleles at polymorphism rs72689561 (SEQ ID NO: 69), two C alleles at polymorphism rs7038893 (SEQ ID NO: 70), and two T alleles at polymorphism rs112935616 (SEQ ID NO: 71).

28. 28. The method of any one of claims 21 to 27, wherein the genotype of the patient comprises one or two C alleles at polymorphism rs7038893 (SEQ ID NO: 70).

29. 29. The method of any one of claims 21 to 28, wherein the genotype of the patient further comprises at least one allele of, or at least one polymorphism in linkage disequilibrium with, at least one Cluster 2 polymorphism as defined in Table 1, and / or the genotype further comprises at least one allele of, or at least one polymorphism in linkage disequilibrium with, at least one Cluster 3 polymorphism as defined in Table 2.

30. 30. The method of any one of claims 1 to 29, wherein the polymorphism in linkage disequilibrium with the cluster 2, 3 or 1 polymorphism has a D' value of 0.4, optionally 0.6 or greater.

31. 31. The method of claim 30, wherein the D' value is 0.8 or greater.

32. The method of any one of claims 1 to 31, wherein the genotype of the patient does not include a C allele at polymorphism rs370820588 (SEQ ID NO: 75), a C allele at polymorphism rs143215670 (SEQ ID NO: 76), an A allele at polymorphism rs343478 (SEQ ID NO: 77), a C allele at polymorphism rs146597587 (SEQ ID NO: 79), and / or a T allele at polymorphism rs10975519 (SEQ ID NO: 80).

33. The method of any one of claims 1 to 32, wherein the genotype of the patient does not include two C alleles at polymorphism rs370820588 (SEQ ID NO: 75), two C alleles at polymorphism rs143215670 (SEQ ID NO: 76), two A alleles at polymorphism rs343478 (SEQ ID NO: 77), two C alleles at polymorphism rs146597587 (SEQ ID NO: 79), and / or two T alleles at polymorphism rs10975519 (SEQ ID NO: 80).

34. 1. A composition comprising an IL-33 axis binding antagonist for use in treating a patient with asthma, wherein the genotype of the patient to be treated has been determined to include at least one allele of a Cluster 2 polymorphism as defined in Table 1 or an equivalent allele of a polymorphism in linkage disequilibrium with a Cluster 2 polymorphism as defined in Table 1.

35. 1. Use of an IL-33 axis binding antagonist in the manufacture of a medicament for use in treating a patient suffering from asthma, wherein the genotype of the patient to be treated has been determined to include at least one allele of a Cluster 2 polymorphism as defined in Table 1, or an equivalent allele of a polymorphism that is in linkage disequilibrium with a Cluster 2 polymorphism as defined in Table 1.

36. 1. A composition comprising an IL-33 axis binding antagonist for use in treating a patient with asthma, wherein the genotype of the patient to be treated has been determined to include at least one allele of a Cluster 3 polymorphism as defined in Table 2, or an equivalent allele of a polymorphism in linkage disequilibrium with a Cluster 3 polymorphism as defined in Table 2.

37. 1. Use of an IL-33 axis binding antagonist in the manufacture of a medicament for use in treating a patient suffering from asthma, wherein the genotype of the patient to be treated has been determined to include at least one allele of a Cluster 3 polymorphism as defined in Table 2, or an equivalent allele at a polymorphism in linkage disequilibrium with a Cluster 3 polymorphism as defined in Table 2.

38. 1. A composition comprising an IL-33 axis binding antagonist for use in treating a patient having asthma, wherein the genotype of the patient to be treated has been determined to comprise at least one allele of a Cluster 1 polymorphism as defined in Table 3, or an equivalent allele of a polymorphism in linkage disequilibrium with a Cluster 1 polymorphism as defined in Table 3.

39. 10. Use of an IL-33 axis binding antagonist in the manufacture of a medicament for use in treating a patient suffering from asthma, wherein the genotype of the patient to be treated has been determined to include at least one allele of a Cluster 1 polymorphism as defined in Table 3, or an equivalent allele of a polymorphism that is in linkage disequilibrium with a Cluster 1 polymorphism as defined in Table 3.

40. The composition for use or use according to any one of claims 34 to 39, wherein the asthma is early onset asthma.

41. The composition for use or use described in any one of claims 34 to 40, wherein the genotype of the patient does not include the C allele at polymorphism rs370820588 (SEQ ID NO: 75), the C allele at polymorphism rs143215670 (SEQ ID NO: 76), the A allele at polymorphism rs343478 (SEQ ID NO: 77), the G allele at polymorphism rs10118776 (SEQ ID NO: 78), the C allele at polymorphism rs146597587 (SEQ ID NO: 79), the T allele at polymorphism rs10975519 (SEQ ID NO: 80) and / or the G allele at polymorphism rs10815381 (SEQ ID NO: 81).

42. The composition for use or use described in any one of claims 34 to 41, wherein the genotype of the patient does not include two C alleles at polymorphism rs370820588 (SEQ ID NO: 75), two C alleles at polymorphism rs143215670 (SEQ ID NO: 76), two A alleles at polymorphism rs343478 (SEQ ID NO: 77), two G alleles at polymorphism rs10118776 (SEQ ID NO: 78), two C alleles at polymorphism rs146597587 (SEQ ID NO: 79), two T alleles at polymorphism rs10975519 (SEQ ID NO: 80) and / or two G alleles at polymorphism rs10815381 (SEQ ID NO: 81).

43. The method, composition for use, or use according to any one of claims 1 to 42, wherein the IL-33 binding antagonist is an IL-33 binding antagonist, an ST-2 binding antagonist, or an IL-1RAcP binding antagonist.

44. The method, composition for use or use of any one of claims 1 to 43, wherein said IL-33 binding antagonist is an antibody or an antigen-binding fragment thereof.

45. The method, composition for use, or use according to any one of claims 1 to 44, wherein the IL-33 binding antagonist is an anti-IL-33 antibody or an antigen-binding fragment thereof.

46. The method, composition for use, or use of claim 45, wherein the anti-IL-33 antibody or antigen-binding fragment thereof comprises a VHCDR1 having the sequence of SEQ ID NO: 37, a VHCDR2 having the sequence of SEQ ID NO: 38, a VHCDR3 having the sequence of SEQ ID NO: 39, a VLCDR1 having the sequence of SEQ ID NO: 40, a VLCDR2 having the sequence of SEQ ID NO: 41, and a VLCDR3 having the sequence of SEQ ID NO: 42.

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