9p21 is a Shared Susceptibility Locus Strongly for Coronary Artery Disease and Weakly for Ischemic Stroke in Chinese Han Population

Abstract

Background— Recent studies on genome-wide association have identified common variants on chromosome 9p21 associated with coronary artery disease (CAD). Given that ischemic stroke and CAD share several aspects of etiology and pathogenesis, we investigated the association of variants on chromosome 9p21 with ischemic stroke and CAD in the Chinese Han population by capturing the majority of diversity in this locus using haplotype-tagging single-nucleotide polymorphisms. Methods and Results— We performed a shared control-cases study using 15 tagging single-nucleotide polymorphisms and 2 previously reported susceptibility single-nucleotide polymorphisms spanning 58 kb of the chromosome of 9p21 in a set of 558 patients with ischemic stroke, 510 patients with CAD, and 557 unaffected participants (controls) in the Chinese Han population. The association analyses were performed at both SNP and haplotype levels. We further verified our findings in an independent cohort of 442 ischemic stroke cases and 502 control subjects. In the first study, rs2383206, rs1004638, and rs10757278 in block 3 were significantly associated with CAD but not with ischemic stroke independent of traditional cardiovascular risk factors in additive model ( P =0.002 to 0.0001, q=0.026 to 0.004). Analysis from all blocks revealed that haplotype profiles of block 3 on 9p21 were significantly different between shared control and cases of CAD ( P =1.3�10 −10 , q=1.2�10 −9 ) and ischemic stroke ( P =1.7�10 −6 , q=7.7�10 −6 ). In the expanded second case-control study, block 3 on 9p21 remained associated with ischemic stroke ( P =2.6�10 −4 , q=6.3�10 −4 ). Conclusions— Our results suggest for the first time that 9p21 is a shared susceptibility locus, strongly for CAD and weakly for ischemic stroke, in a Chinese Han population.