Genetic polymorphisms associated with cardiovascular disorders and drug response, methods of detection and uses thereof

Abstract

The present invention is based on the discovery of genetic polymorphisms that are associated with cardiovascular disorders, particularly acute coronary events such as myocardial infarction and stroke, and genetic polymorphisms that are associated with responsiveness of an individual to treatment of cardiovascular disorders with statin. In particular, the present invention relates to nucleic acid molecules containing the polymorphisms, variant proteins encoded by such nucleic acid molecules, reagents for detecting the polymorphic nucleic acid molecules and proteins, and methods of using the nucleic acid and proteins as well as methods of using reagents for their detection.

Description

FIELD OF THE INVENTION[0001]The present invention is in the field of cardiovascular disorders and drug response, particularly acute coronary events and statin treatment of acute coronary events. In particular, the present invention relates to specific single nucleotide polymorphisms (SNPs) in the human genome, and their association with acute coronary events and / or variability in the responsiveness to statin treatment (including preventive treatment) between different individuals. The naturally-occurring SNPs disclosed herein can be used as targets for the design of diagnostic reagents and the development of therapeutic agents, as well as for disease association and linkage analysis. In particular, the SNPs of the present invention are useful for, for example, identifying whether an individual is likely to experience an acute coronary event (either a first or recurrent acute coronary event), for predicting the seriousness or consequences of an acute coronary event in an individual, ...

AI Technical Summary

Benefits of technology

The present invention provides novel SNPs, unique combinations of these SNPs, and haplotypes associated with cardiovascular disorders, particularly acute coronary events, and the response to statin treatment. These SNPs can be used as diagnostic markers and therapeutic targets for the development of diagnostic reagents and therapeutic agents. The invention also provides methods for detecting and measuring these SNPs, as well as methods for selecting and formulating treatment regimes based on an individual's genotype. The SNPs are useful for predicting the risk of cardiovascular disease and the response to statin treatment.

Problems solved by technology

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.

A second type of vulnerable plaque morphology, known as “plaque erosion”, can also lead to a fatal coronary thrombotic event.

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).

Despite a very high prevalence and lifetime risk of MI, there are no good prognostic markers that can identify an individual with a high risk of vulnerable plaques and justify preventive treatments.

Despite showing some promise, 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.

In each case, a cascade of cellular changes due to ischemia or increased cranial pressure leads to injuries or death of the brain cells.

The hemorrhagic strokes, although less prevalent, pose a greater danger.

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

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

While the incidence of muscle side effects are low, the most serious side effect, myositis with rhabdomyolysis, is life threatening.

Nevertheless, cardiovascular diseases remain the major cause of death in industrialized countries, at least in part due to the presence of highly prevalent risk factors and insufficient treatment (Wong, M. D., et al., Contribution of major diseases to disparities in mortality.

Even with appropriate therapy, not all patients respond equally well to statin treatment.

Despite the overwhelming evidence that statins decrease risk for cardiovascular disease, both in primary and secondary intervention settings, statin therapy clearly only achieves partial risk reduction.

As indicated above, severe myopathies represent a significant risk for a low percentage of the patient population.

More aggressive statin therapy will likely increase the incidence of the above adverse events as well as elevate the cost of treatment.

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

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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