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Objectives:  In contrast to coronary heart disease (CHD), genetic variants that influence susceptibility to peripheral arterial disease (PAD) remain largely unknown.   Background:  We performed a two-stage genomic association study leveraging an electronic medical record (EMR) linked-biorepository to identify genetic variants that mediate susceptibility to PAD.   Methods:  PAD was defined as a resting/post-exercise ankle-brachial index (ABI) ≤0.9 or ≥1.4 and/or history of lower extremity revascularization. Controls were patients without history of PAD. In Stage I we performed a genome-wide association analysis adjusting for age and sex, of 537, 872 SNPs in 1641 PAD cases (66 ± 11 years, 64% men) and 1604 control subjects (61 ± 7 year, 60% men) of European ancestry. In Stage II we genotyped the top 48 SNPs that were associated with PAD in Stage I, in a replication cohort of 740 PAD cases (70 ± 11 year, 63% men) and 1051 controls (70 ± 12 year, 61% men).   Results:  The SNP rs653178 in the  ATXN2-SH2B3  locus was significantly associated with PAD in the discovery cohort ( OR  = 1.23;  P  = 5.59 × 10 −5 ), in the replication cohort ( OR  = 1.22; 8.9 × 10 −4 ) and in the combined cohort ( OR  = 1.22;  P  = 6.46 × 10 −7 ). In the combined cohort this SNP remained associated with PAD after additional adjustment for cardiovascular risk factors including smoking ( OR  = 1.22;  P  = 2.15 × 10 −6 ) and after excluding patients with ABI > 1.4 ( OR  = 1.24;  P  = 3.98 × 10 −7 ). The SNP is in near-complete linkage disequilibrium (LD) ( r  2  = 0.99) with a missense SNP (rs3184504) in  SH2B3 , a gene encoding an adapter protein that plays a key role in immune and inflammatory response pathways and vascular homeostasis. The SNP has pleiotropic effects and has been previously associated with multiple phenotypes including myocardial infarction.   Conclusions:  Our findings suggest that the  ATXN2-SH2B3  locus influences susceptibility to PAD.

The ATXN2-SH2B3 locus is associated with peripheral arterial disease: an electronic medical record-based genome-wide association study