Deficient CDKN2B Expression: A Double Hit for PAD.

In 2007, multiple independent groups, using genome-wide association studies, made a significant breakthrough in the field of cardiovascular genetics when they identified a coronary artery disease risk locus on chromosome 9p21. Subsequently, additional studies examining a wide variety of patient cohorts have linked single-nucleotide polymorphisms (SNPs) within chromosome 9p21 to several cardiovascular diseases, including myocardial infarction, stroke, aneurysms, and peripheral artery disease (PAD).1 Importantly and perhaps unexpectedly, genetic variation at chromosome 9p21 has been shown to modify PAD risk independent of conventional atherosclerotic risk factors or pre-existent myocardial infarction.2,3 Although rates of coronary artery disease and first myocardial infarction may be decreasing,4 PAD is showing no evidence of a decline, and with roughly 1/5 of the population carrying 2 copies of the 9p21 risk allele,5 a role for this locus in PAD pathogenesis is intriguing. Article, see p 230 Enthusiasm over chromosome 9p21 was tempered by the reality that the roughly 58-kb haplotype block identified by the aforementioned genome-wide association studies lies within a region devoid of any protein-coding genes. The closest protein-coding genes lie a few kilobase proximal as part of the INK4/ARF locus.1 This locus contains the cyclin-dependent kinase inhibitors (CDKNs), CDKN2A and CDKN2B, as well as p14/ARF, a splice variant of CDKN2A. Could one of these genes be responsible for increased cardiovascular disease risk linked to the 9p21 locus? Previous studies investigating CDKN2B have been promising, as its expression has been shown to be reduced in atherosclerotic plaques in human carriers of the 9p21 risk allele.6 In extending this knowledge, studies by Deloukas et al6 and Leeper et al7 used CDKN2B−/− mice to demonstrate increased smooth muscle cell (SMC) apoptosis and decreased SMC phagocytic clearance in mouse models of aneurysm and atherosclerosis, respectively. In the study …