Large scale association analysis for identification of genes underlying premature coronary heart disease: cumulative perspective from analysis of 111 candidate genes

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Abstract
Background: to date, only three groups have reported data from large scale genetic association studies of coronary heart disease using a case control design. Methods and results: to extend our initial report of 62 genes, we present data for 210 polymorphisms in 111 candidate genes genotyped in 352 white subjects with familial, premature coronary heart disease (onset age for men, 45; for women, 50) and a random sample of 418 population based whites. Multivariate logistic regression analysis was used to compare the distributions of genotypes between cases and the comparison group while controlling for age, sex, body mass, diabetes, and hypertension. Significant associations were found with polymorphisms in thrombospondin-4 (THBS4), thrombospondin-2 (THBS2) and plasminogen activator inhibitor-2 (PAI2), the strongest being with the A387P variant in THBS4 (p = 0.002). The THBS2 and THBS4 associations have since been replicated. We evaluated polymorphisms in 40 genes previously associated with coronary heart disease and found significant (pConclusions: despite known caveats of genetic association studies, they can be an effective means of hypothesis generation and complement classic linkage studies for understanding the genetic basis of coronary heart disease.

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