Genetic polymorphisms associated with statin response and cardiovascular diseases, methods of detection and uses thereof

Abstract

The present invention provides compositions and methods based on genetic polymorphisms that are associated with response to statin treatment, particularly for reducing the risk of cardiovascular disease, especially coronary heart disease (such as myocardial infarction) and stroke. For example, the present invention relates to nucleic acid molecules containing the polymorphisms, variant proteins encoded by these nucleic acid molecules, reagents and kits for detecting the polymorphic nucleic acid molecules and variant proteins, and methods of using the nucleic acid molecules and proteins as well as methods of using reagents and kits for their detection.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation application of U.S. non-provisional application Ser. No. 13 / 085,955, dated Apr. 13, 2011, which claims the benefit of U.S. provisional application Ser. No. 61 / 325,689 filed Apr. 19, 2010, U.S. provisional application Ser. No. 61 / 332,509 filed May 7, 2010, and U.S. provisional application Ser. No. 61 / 405,972 filed Oct. 22, 2010, the contents of each of which are hereby incorporated by reference in their entirety into this application.FIELD OF THE INVENTION[0002]The present invention is in the field of drug response and disease risk, particularly genetic polymorphisms that are associated with response to statins, especially for the prevention or treatment of cardiovascular diseases (CVD) such as coronary heart disease (CHD) (which includes coronary events such as myocardial infarction (MI)) and cerebrovascular events (such as stroke). In particular, the present invention relates to specific single nucleoti...

AI Technical Summary

Benefits of technology

[0049]Exemplary embodiments of the present invention further provide methods for selecting or formulating a treatment regimen (e.g., methods for determining whether or not to administer statin treatment to an individual having CVD, or who is at risk for developing CVD in the future, or who has previously had CVD, methods for selecting a particular statin-based treatment regimen such as dosage and frequency of administration of statin, or a particular form / type of statin such as a particular pharmaceutical formulation or statin compound, methods for administering (either in addition to or instead of a statin) an alternative, non-statin-based treatment, such as niacin, fibrates, or ezetimibe (e.g., Zetia® or Ezetrol®), to individuals who are predicted to be unlikely to respond positively to statin treatment, etc.), and methods for determining the likelihood of experiencing toxicity or other undesirable side effects from statin treatment, etc. Various embodiments of the present invention also provide methods for selecting individuals to whom a statin or other therapeutic will be administered based on the individual's genotype, and methods for selecting individuals for a clinical trial of a statin or other therapeutic agent based on the genotypes of the individuals (e.g., selecting individuals to participate in the trial who are most likely to respond positively from the statin treatment and / or excluding individuals from the trial who are unlikely to respond positively from the statin treatment based on their SNP genotype(s), or selecting individuals who are unlikely to respond positively to statins based on their SNP genotype(s) to participate in a clinical trial of another type of drug that may benefit them). Further embodiments of the present invention provide methods for reducing an individual's risk of developing CVD (such as CHD (e.g., MI) or stroke) using statin treatment, including preventing recurring CVD (e.g., recurrent MI) using statin treatment, when said individual carries one or more SNPs identified herein as being associated with statin response.

[0051]In certain exemplary embodiments, the invention provides methods for identifying an individual who has an altered likelihood of responding to statin treatment or an altered risk for developing CVD, particularly CHD or stroke (including, for example, a first incidence and / or a recurrence of the disease, such as primary or recurrent MI), in which the method comprises detecting a single nucleotide polymorphism (SNP) in any one of the nucleotide sequences of SEQ ID NOS:1-51, SEQ ID NOS:103-176, SEQ ID NOS:177-622, and SEQ ID NOS:623-3661 in said individual's nucleic acids, wherein the SNP is specified in Table 1 and / or Table 2, and the presence of the SNP is indicative of an altered response to statin treatment of an altered risk for CVD in said individual. In certain embodiments, the CVD is CHD, particularly MI. In certain other embodiments, the CVD is stroke. In certain exemplary embodiments of the invention, SNPs that occur naturally in the human genome are provided within isolated nucleic acid molecules. These SNPs are associated with response to statin treatment thereby reducing the risk of CVD, such as CHD (e.g., MI) or stroke, such that they can have a variety of uses in the diagnosis, prognosis, treatment, and / or prevention of CVD, and particularly in the treatment or prevention of CVD using statins. In certain embodiments, a nucleic acid of the invention is an amplified polynucleotide, which is produced by amplification of a SNP-containing nucleic acid template. In another embodiment, the invention provides for a variant protein that is encoded by a nucleic acid molecule containing a SNP disclosed herein.

[0054]In certain embodiments, the presence of a statin response allele disclosed herein in Tables 4-22 (an allele associated with increased response to statin treatment for reducing CVD or CHD risk) is detected and indicates that an individual has an increased risk for developing CVD, such as CHD (e.g., MI) or stroke. In these embodiments, in which the same allele is associated with both increased risk for developing CVD and increased response to statin treatment (i.e., the same allele is both a risk and a response allele), this increased risk for developing CVD can be reduced by administering statin treatment to an individual having the allele.

Problems solved by technology

The resultant increase in LDL catabolism results in decreased circulating LDL, a major risk factor for cardiovascular disease.

Similarly, in individuals who are less likely to benefit from a drug but are at risk for adverse events, use of the drug in these individuals can be de-prioritized or delayed.

The luminal narrowing or blockage of coronary arteries reduces oxygen and nutrient supply to the cardiac muscle (cardiac ischemia), leading to myocardial necrosis and / or stunning.

A vulnerable plaque is a plaque, often not stenotic, that has a high likelihood of becoming disrupted or eroded, thus forming a thrombogenic focus.

However, due to the asymptomatic nature of 25% of acute MIs (absence of atypical chest pain, low ECG sensitivity), a significant portion of MIs are not diagnosed and therefore not treated appropriately (e.g., prevention of recurrent MIs).

These markers have significant limitations such as low specificity and low positive predictive value, and the need for multiple reference intervals to be used for different groups of people (e.g., males-females, smokers-non smokers, hormone replacement therapy users, different age groups).

These limitations diminish the utility of such markers as independent prognostic markers for MI screening.

Individuals who experience early-onset MI may not be effectively identified by current cholesterol treatment guidelines, such as those suggested by the National Cholesterol Education Program.

Stroke occurs when an artery bringing oxygen and nutrients to the brain either ruptures, causing hemorrhagic stroke, or gets occluded, causing ischemic stroke.

In both ischemic and hemorrhagic stroke, a cascade of cellular changes due to ischemia or increased cranial pressure leads to injuries or death of the brain cells.

The hemorrhagic stroke, although less prevalent, poses a greater danger.

Symptoms can include: numbness or weakness in the face, arm, or leg, especially on one side of the body; confusion or difficulty in talking or understanding speech; trouble seeing in one or both eyes; and difficulty with walking, dizziness, or loss of balance and coordination”.

The acute nature of stroke leaves physicians with little time to prevent or lessen the devastation of brain damage.

Additionally, the effects of a variant form may be both beneficial and detrimental, depending on the environment.

For example, a heterozygous sickle cell mutation confers resistance to malaria, but a homozygous sickle cell mutation is usually lethal.

A nonsense mutation results in a type of non-synonymous codon change in which a stop codon is formed, thereby leading to premature termination of a polypeptide chain and a truncated protein.

Furthermore, in the case of nonsense mutations, a SNP may lead to premature termination of a polypeptide product.

Such variant products can result in a pathological condition, e.g., genetic disease.

Clinical trials have shown that patient response to treatment with pharmaceuticals is often heterogeneous.

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