RISK OF VASCULAR DISEASE IN CBS HETEROZYGOTES

Fox Chase Cancer Center, Philadelphia PA

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Abstract

Individuals with plasma levels of homocyst(e)ine in the top five percent of the population have hyperhomocyst(e)inemia, a condition associated with cardiovascular, cerebrovascular, and peripheral vascular disease. One cause of hyperhomocyst(e)inemia is mutation in the cystathionine beta synthase gene (CBS). Individuals with two mutant CBS alleles have clinical CBS deficiency and have extremely high levels of plasma homocyst(e)ine. Individuals with one mutant CBS allele tend to have moderate hyperhomocyst(e)inemia. Based on the frequency of clinical CBS deficiency, there are at least 1,000,000 CBS heterozygotes in the USA. The risk of vascular disease in these individuals is not known. The overall goal of this work is to identify CBS heterozygotes and determine the extent to which they are at increased risk for hyperhomocyst(e)inemia and vascular disease. We have three specific aims in this project. First, we will develop a technology which can rapidly and efficiently determine CBS allele frequency in population studies. This will involve refinement and improvement of our yeast CBS assay for mutation detection in human CBS. Second, we will determine the allele frequency in the general population by identification of CBS heterozygotes in 1,200 random individuals using the yeast CBS assay. We will also characterize these mutant alleles both at the molecular and functional levels. Finally, we will determine the mutant CBS allele frequency in 1,200 individuals diagnosed with coronary artery disease (CAD). Comparison of the mutant allele frequency between the CAD group and the controls will allow us to determine the relative risk of CAD in CBS heterozygotes.