Genome-Wide Mapping of Susceptibility to Coronary Artery Disease Identifies a Novel Replicated Locus on Chromosome 17

Abstract

Coronary artery disease (CAD) is a leading cause of death world-wide, and most cases have a complex, multifactorial aetiology that includes a substantial heritable component. Identification of new genes involved in CAD may inform pathogenesis and provide new therapeutic targets. The PROCARDIS study recruited 2,658 affected sibling pairs (ASPs) with onset of CAD before age 66 y from four European countries to map susceptibility loci for CAD. ASPs were defined as having CAD phenotype if both had CAD, or myocardial infarction (MI) phenotype if both had a MI. In a first study, involving a genome-wide linkage screen, tentative loci were mapped to Chromosomes 3 and 11 with the CAD phenotype (1,464 ASPs), and to Chromosome 17 with the MI phenotype (739 ASPs). In a second study, these loci were examined with a dense panel of grid-tightening markers in an independent set of families (1,194 CAD and 344 MI ASPs). This replication study showed a significant result on Chromosome 17 (MI phenotype; p = 0.009 after adjustment for three independent replication tests). An exclusion analysis suggests that further genes of effect size λ_sib > 1.24 are unlikely to exist in these populations of European ancestry. To our knowledge, this is the first genome-wide linkage analysis to map, and replicate, a CAD locus. The region on Chromosome 17 provides a compelling target within which to identify novel genes underlying CAD. Understanding the genetic aetiology of CAD may lead to novel preventative and/or therapeutic strategies. Coronary artery disease (CAD), which presents clinically as a heart attack (myocardial infarction) or angina, is a leading cause of death world-wide. The aetiology of CAD is complex with a substantial heritable component. Although there is a huge knowledge-base detailing many aspects of the underlying pathophysiology of CAD, it is likely that undiscovered pathways exist. Positional cloning projects can identify novel susceptibility genes; in the first step genome-wide linkage screens are used to assign loci to specific chromosomes. The authors have collected 2,036 CAD families from four European countries, in order to maximise the power of detecting genes that confer modest risks. A genome-wide linkage scan identified three promising regions for intensive study; one of the linked regions (Chromosome 17) was confined to families with multiple cases of myocardial infarction and was replicated in a second independent series of families. In addition the linkage scan confirmed a previously identified locus on Chromosome 2. These results demonstrate that novel CAD susceptibility genes are tractable to positional cloning which promises to lead to the identification of new molecular insights into this condition, and hopefully, new treatments.