Enduring Mystery of the Chromosome 9p21.3 Locus
Out of the long list of genetic loci that have been discovered by genome-wide association studies to be associated with a variety of clinical traits and diseases, one of the earliest such discoveries remains one of the most tantalizing. In 2007, 3 groups independently reported a locus on chromosome 9p21.3 to be associated with coronary artery disease (CAD), a finding that has been replicated by dozens of subsequent studies and seems to represent the single most important population-wide genetic risk factor for CAD. Especially noteworthy is that the locus has not been linked to any of the traditional CAD-risk factors, suggesting that the locus represents a novel pathogenetic mechanism that could potentially be exploited to develop an entirely new class of therapeutics.
A study by Harismendy et al1 attempted to address this putative mechanism using a combination of genetic and epigenetic datasets to identify potential transcriptional regulatory elements in the locus, focusing on 1 element in which 2 linked index SNPs were predicted to create (non-CAD-risk alleles) versus disrupt (CAD-risk alleles) a canonical STAT1 transcription factor binding site. Experiments in cultured HeLa cells, human umbilical vein endothelial cells …