AUTHOR=Kullo Iftikhar J. , Shameer Khader , Jouni Hayan , Lesnick Timothy G. , Pathak Jyotishman , Chute Christopher G. , de Andrade Mariza 

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

JOURNAL=Frontiers in Genetics

VOLUME=5

YEAR=2014

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2014.00166

DOI=10.3389/fgene.2014.00166

ISSN=1664-8021

ABSTRACT=<p><bold>Objectives:</bold> In contrast to coronary heart disease (CHD), genetic variants that influence susceptibility to peripheral arterial disease (PAD) remain largely unknown.</p><p><bold>Background:</bold> 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.</p><p><bold>Methods:</bold> 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).</p><p><bold>Results:</bold> The SNP rs653178 in the <italic>ATXN2-SH2B3</italic> locus was significantly associated with PAD in the discovery cohort (<italic>OR</italic> = 1.23; <italic>P</italic> = 5.59 × 10<sup>−5</sup>), in the replication cohort (<italic>OR</italic> = 1.22; 8.9 × 10<sup>−4</sup>) and in the combined cohort (<italic>OR</italic> = 1.22; <italic>P</italic> = 6.46 × 10<sup>−7</sup>). In the combined cohort this SNP remained associated with PAD after additional adjustment for cardiovascular risk factors including smoking (<italic>OR</italic> = 1.22; <italic>P</italic> = 2.15 × 10<sup>−6</sup>) and after excluding patients with ABI &gt; 1.4 (<italic>OR</italic> = 1.24; <italic>P</italic> = 3.98 × 10<sup>−7</sup>). The SNP is in near-complete linkage disequilibrium (LD) (<italic>r</italic><sup>2</sup> = 0.99) with a missense SNP (rs3184504) in <italic>SH2B3</italic>, 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.</p><p><bold>Conclusions:</bold> Our findings suggest that the <italic>ATXN2-SH2B3</italic> locus influences susceptibility to PAD.</p>