Chromosome 9p21 and Cardiovascular Disease

The middle of 2007 saw what may, with time, turn out to be the single most important discovery in the genetics of cardiovascular diseases. Within a few weeks, 4 independent genomewide association studies reported the association of the same locus on chromosome 9p21 with coronary artery disease (CAD) and myocardial infarction (MI).1–4 In fact, of the hundreds of thousands single-nucleotide polymorphisms studied across the genome the same locus showed the strongest association with CAD in all 4 studies, as illustrated by a direct comparison of the data from the Wellcome Trust Case Control Consortium and the Cardiogenics Consortium.4 The finding has led to a plethora of further studies that have largely confirmed the association of the 9p21 locus with CAD and MI in both case–control and cohort studies and in multiple ethnic groups.5–12 9p21 represents the most replicated locus for CAD and MI to date. The risk allele as currently defined, until causal variants are identified, is common (allele frequency of almost 50%) and associated with a 20% to 30% increased risk per copy. The effect of the 9p21 locus on CAD and MI risk is unaltered by adjustment for traditional cardiovascular risk factors5,6 and indeed studies in healthy populations have found no explanatory effect of the 9p21 locus on CAD risk via blood pressure, cholesterol levels, body mass index, or smoking behavior.13Article see p 85 The chromosome 9p21 locus is intriguing for several reasons. First, it is a region well known in cancer genetics as one of the most common sites of deletions leading to hereditary forms of cutaneous malignant melanoma.14 Second, the association signal for CAD maps to a segment with no known protein coding genes.4 Indeed, the most strongly associated single-nucleotide polymorphisms lie almost a 100 kb from the …