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

The present invention provides methods for selecting or formulating a treatment regimen for individuals with CVD or who are at risk for developing CVD based on their genotype. The invention also provides methods for administering alternative treatments to individuals who are predicted to be non-responsive to statin treatment. The invention also provides methods for reducing an individual's risk of developing CVD, particularly CHD or stroke, by identifying an altered likelihood of responding to statin treatment or increased risk for CVD based on the presence of specific gene variants. The invention can be used for diagnosis, prognosis, treatment, and prevention of CVD, particularly using statins.

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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