Identifying genes for coronary artery disease: An idea whose time has come.

Coronary artery disease (CAD) remains the number one killer in the western world. Genetics accounts for greater than 50% of the risk for CAD. Genetic screening and early prevention in individuals identified as being at increased risk could dramatically reduce the prevalence of CAD, thus necessitating the identification of genes predisposing to CAD. Studies of genes identified by the candidate gene approach have not been replicated due, in part, to inadequate sample size. Genome-wide scan association studies have been limited by the use of thousands of markers rather than the hundreds of thousands required, and by the use of hundreds of individuals rather than the thousands required. Replication of positive findings in an independent population is essential. To detect a minor allele frequency of 5% or greater with an odds ratio for risk of 1.3 or greater and 90% power, an estimated 14,000 (9000 affected and 5000 control) subjects are required.The Affymetrix GeneChip Human Mapping 500K Array Set (Affymetrix Inc, USA) provides a marker every 6000 base pairs as required, and is being used to genotype 1000 cases of premature CAD and 1000 normal subjects, followed by replication in 8000 affected individuals and 4000 control subjects. The phenotype is confirmed or excluded by coronary arteriograms by catheterization or multislice computed tomography.Since 2005, more than 800 million genotypes have been performed and analyses performed on 500 control subjects and 500 affected individuals. Several thousand significant single nucleotide polymorphisms and 130 clusters associated with CAD have been identified.This is the first genome-wide scan using the 500,000 marker set in a case-control association study for CAD genes. Several genes associated with CAD appear promising.