The human genome and prospects for management of cardiovascular disease

Abstract

High throughput technology to map genes predisposing to polygenic disorders such as coronary artery disease (CAD) has been lacking until recently. HapMap made available the hundreds of thousands of markers required, namely single nucleotide polymorphism (SNPs), to perform high-density genome-wide association studies. The AffyMetrix (USA) platform with 500,000 SNPs and, more recently, 1,000,000 SNPs initiated a new era in the mapping of genes for polygenic disorders. Comprehensive prevention of CAD will require knowledge of the genetic as well as the environmental components of risk factors. It is estimated from epidemiological studies that genetic factors account for approximately 50% of susceptibility. The first genome-wide association study performed for CAD identified 9p21 as risk region. This risk allele occurs in approximately 75% of all Caucasians; of this group, it is homozygous in 25% and heterozygous in the remaining. Homozygotes have a 40% increased risk for CAD, and heterozygotes have a 15% to 20% increased risk. The 9p21 region initially detected in a total population of 23,000 Caucasians has since been confirmed by at least three independent studies showing similar frequency and risk for CAD and/or myocardial infarction. In addition to being very common, this risk allele is independent of known risk factors such as cholesterol, hypertension or diabetes. This implies a new mechanism contributing to CAD and new targets to develop novel therapy. The 9p21 region does not appear to have any genes coding for protein but it does contain antisense noncoding RNA.