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

In contrast to coronary heart disease (CHD), genetic variants that influence susceptibility to peripheral arterial disease (PAD) remain largely unknown.

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.

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).

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.

Our findings suggest that the ATXN2-SH2B3 locus influences susceptibility to PAD.