Genetic polymorphisms associated with coronary stenosis, methods of detection and uses thereof

Abstract

The present invention is based on the discovery of genetic polymorphisms that are associated with coronary stenosis. 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 acids and proteins as well as methods of using reagents for their detection.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a divisional application of U.S. non-provisional application Ser. No. 10 / 741,601, filed Dec. 22, 2003, which claims priority to provisional application Ser. No. 60 / 434,741, filed Dec. 20, 2002, provisional application Ser. No. 60 / 453,050, filed Mar. 10, 2003, and provisional application Ser. No. 60 / 466,437, filed Apr. 30, 2003, the contents of which are hereby incorporated by reference in its entirety into this application.FIELD OF THE INVENTION [0002] The present invention is in the field of stenosis diagnosis and therapy. In particular, the present invention relates to specific single nucleotide polymorphisms (SNPs) in the human genome, and their association with stenosis and related pathologies. Based on differences in allele frequencies in the stenosis patient population relative to normal individuals, the naturally-occurring SNPs disclosed herein can be used as targets for the design of diagnostic reagents and t...

AI Technical Summary

Benefits of technology

The present invention provides novel SNPs, unique combinations of these SNPs, and haplotypes associated with stenosis and related pathologies. These SNPs can be used as targets for the development of diagnostic reagents and therapeutic agents for stenosis. The invention also provides methods for detecting and identifying these SNPs, as well as methods for screening and identifying therapeutic agents. Overall, the invention provides useful information for the diagnosis, treatment, and prevention of stenosis.

Problems solved by technology

Coronary stenosis is frequently a deadly disease.

It is a major underlying cause of coronary heart disease (CHD), which is the single largest cause of death in the U.S. Over half a million coronary deaths, including 250,000 sudden cardiac deaths, occur each year in U.S. Coronary stenosis is also a costly disease.

Still, these statistics underestimate the true prevalence of the disease since coronary stenosis often remains clinically asymptomatic for decades, and only becomes symptomatic when the disease has progressed to a severe, and sometime fatal, state.

However, risk assessments and EKGs are imperfect diagnostic tests for stenosis since they can be both insensitive (giving false negatives) and non-specific (giving false positives).

Coronary arteriography is the definitive test for assessing the severity of coronary stenosis, however, it is not very sensitive in early detection of mild stenosis.

It is also an invasive procedure with a small risk of death due to the catheterization procedure and the contrast dye.

Because of this risk, it is typically only used at a time when coronary stenosis is considered likely from symptoms or other tests, which is hardly an ideal time to start intervention.

Although many risk factors for coronary stenosis have been identified, including age, diabetes, hypertension, high serum cholesterol, smoking, etc., and genetic factors play significant roles in several of these risk factors, significant genetic risk factors are likely to exist which have not been identified to date.

Therefore, the presently known risk factors are inadequate for predicting coronary stenosis risk in individuals.

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.