Genomics in coronary artery disease: past, present and future

The past three years has seen the completion of a series of genome-wide association studies designed to identify genetic variants associated with risk for coronary artery disease (CAD) or its related phenotype, myocardial infarction (MI). The first and most robust genetic risk variant is located on chromosome 9p21.3. A series of other loci, with less prevalence and smaller population-attributable risks, were described to associate with CAD/MI. However, these loci explain only a fraction of the heritable component of CAD/MI. A small fraction of these loci alter the function of genes known to be involved in atherogenesis and/or thrombosis. The rest do not appear to impart their risk via any known risk factors, implying yet unknown pathogenetic pathways. Moreover, many loci, including 9p21, are located in intergenic segments and elicit the phenotype by novel mechanisms whose elucidation will most likely unravel novel therapeutic targets. Future investigation will be focused on defining the underlying mechanism by which the phenotype is affected, the role of these genetic markers in standard risk prediction models and identification of further loci to explain the 'missing heritability'.