Abstract 2073: Genome-wide Association Studies of the Ankle-brachial Index: A Meta-analysis of 12 Cohorts Including 28083: Participants
Background: Genes conferring susceptibility to peripheral arterial disease (PAD) remain largely unknown. We conducted a meta-analysis of genome-wide association (GWA) studies to identify genetic variants associated with the ankle-brachial index (ABI).
Methods and Results: Caucasian participants from 12 cohort studies with genotyping and ABI data were examined. Each study imputed data to the 2.5 million HapMap SNPs and conducted GWA studies using additive genetic models to test each SNP for association with continuous ABI (excluding ABI >1.4, linear regression) and with PAD (ABI ≤0.9 vs. ABI >0.9, logistic regression). Phenotypes were adjusted for age and sex. Next, fixed effects meta-analyses based on inverse variance weighting were conducted. There were a total of 28,083 participants (~60% women, mean age 49.7 to 72.3 years) including 2660 participants with PAD. No association for ABI or PAD achieved genome-wide significance (p<5 × 10−8). The strongest association for ABI was rs10225945 on chromosome 7 near the JAZF1 gene (beta 0.009, p=3.21 ×10−7) associated with type 2 diabetes, adult height, endometrial sarcomas and prostate cancer. The JAZF1 gene encodes a nuclear protein that functions as a transcriptional repressor. There were 291 additional SNPs associated with ABI with p<9.9 ×10−5 including 6 SNPs in the chromosome 9p21 region previously associated with coronary disease and diabetes (rs9632884, p=1.36 × 10−5, r2=0.84 with rs1333049). For PAD, rs6811394 on chromosome 4, nearest gene PCDH7, had the strongest association (p=1.28 × 10−6). The PCDH7 gene product is an integral membrane protein believed to play a role in cell-cell recognition and adhesion.
Conclusions: Our investigation identified suggestive genetic associations for ABI near genes/regions previously reported to be associated with diabetes and coronary disease. Additional studies are needed to replicate our findings.