The most notable new finding for CAD is the powerful association on chromosome 9p21.3 (Table 3; Fig. 5). Although the strongest signal is seen at rs1333049 (P=1.8×10-14), associations are seen for SNPs across>100 kilobases. This region has not been highlighted in previous studies of CAD or myocardial infarction40,43. The region of interest contains the coding sequences of genes for two cyclin dependent kinase inhibitors, CDKN2A (encoding p16INK4a) and CDKN2B (p15INK4b), although the most closely associated SNP is some distance removed. Both genes have multiple isoforms, have an important role in the regulation of the cell cycle and are widely expressed44, with CDKN2B known to be expressed in the macrophages but not the smooth muscle cells of fibrofatty lesions45,46. It is of interest that expression of CDKN2B is induced by transforming growth factor beta (TGF-β) and that the TGF-β signalling system is implicated in the pathogenesis of human atherosclerosis45,46. Besides CDKN2A and CDKN2B, the only other known gene nearby is MTAP which encodes methylthioadenosine phosphorylase, an enzyme that contributes to polyamine metabolism and is important for the salvage of both adenine
