title: Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies.
abstract: BACKGROUND
  Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.
  
  
  RESULTS
  Continuous ABI and PAD (ABI ≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (≈60% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β=-0.006, P=2.46×10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65×10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6×10(-5)), CYBA (rs3794624, P=6.3×10(-5)), and rs1122608 (LDLR, P=0.0026).
  
  
  CONCLUSIONS
  Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI.
authors.affiliation: Framingham Heart Study, 73 Mount Wayte Avenue, Framingham, MA 01701, USA. murabito@bu.edu
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mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D055109:Ankle Brachial Index; D002899:Chromosomes, Human, Pair 9; D015331:Cohort Studies; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D060148:HapMap Project; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016491:Peripheral Vascular Diseases / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012737:Sex Factors
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15