Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies

作者:Murabito Joanne M*; White Charles C; Kavousi Maryam; Sun Yan V; Feitosa Mary F; Nambi Vijay; Lamina Claudia; Schillert Arne; Coassin Stefan; Bis Joshua C; Broer Linda; Crawford Dana C; Franceschini Nora; Frikke Schmidt Ruth; Haun Margot; Holewijn Suzanne; Huffman Jennifer E; Hwang Shih Jen; Kiechl Stefan; Kollerits Barbara; Montasser May E; Nolte Ilja M; Rudock Megan E; Senft Andrea; Teumer Alexander; van der Harst Pim; Vitart Veronique; Waite Lindsay L
来源:Circulation-Cardiovascular Genetics, 2012, 5(1): 100-112.
DOI:10.1161/CIRCGENETICS.111.961292

摘要

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. %26lt;br%26gt;Methods and Results-Continuous ABI and PAD (ABI %26lt;= 0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the %26lt;= 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 (approximate to 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 (beta=-0.006, P=2.46x10(-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=2.65x10(-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=3.6x10(-5)), CYBA (rs3794624, P=6.3x10(-5)), and rs1122608 (LDLR, P=0.0026). %26lt;br%26gt;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. (Circ Cardiovasc Genet. 2012;5:100-112.)