Quest for Genes and Mechanisms Linking the Human Chromosome 9p21.3 Locus to Cardiovascular Disease

Abstract

In the past several years, advances in molecular genetics have been adopted as tools to dissect the cause and pathophysiology of common complex diseases and their associated risk factors in a hypothesis-free approach, using the genome-wide association study design and high-density, single nucleotide polymorphism (SNP) genotyping arrays. Starting in 2007 with the discovery of the chromosome 9p21.3 (Chr9p21.3) locus (see recent review),1 major progress has been made in terms of identification of novel susceptibility loci for coronary artery disease (CAD; ie, genomic regions that are strongly and consistently associated with CAD).2,3 These CAD susceptibility loci are of major interest because they are expected to harbor genes constituting important nodes in biological pathways underlying CAD and hence may serve as shortcuts to discovery of hitherto unknown disease mechanisms. However, causal variants will only occasionally be among those that are directly typed in genome-wide association scans, and the interval within which the etiologic variant(s) are expected to lie can be sizeable, and often contains several genes. Thus, the challenge for the next several years will be to move from statistical association based on genetic markers to identification and functional characterization of individual risk-associated genes, gene variants, biological pathways, and proteins and to elucidation of their roles in the resulting vascular pathology. Article see p 1896 In the rapidly expanding group of robustly associated CAD loci, the Chr9p21.3 locus contributes the largest increase in risk, 1 and 2 copies of the risk allele (allele frequency of 0.50) being associated with a rise in CAD risk of around 20% to 40% and 40% to 70%, respectively. Interestingly, this substantial increase in risk is independent of established risk factors, which suggests that the Chr9p21.3 locus operates through an …