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

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

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


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) (r2=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.

Original languageEnglish (US)
Article numberArticle 166
JournalFrontiers in Genetics
Issue numberJUN
StatePublished - 2014


  • Ankle-brachial index
  • Biorepository
  • Electronic medical records
  • Genome-wide association study
  • Peripheral arterial disease

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Genetics(clinical)


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