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

J.M. Murabito, C.C. White, M. Kavousi, Y.V. Sun, M.F. Feitosa, V. Nambi, C. Lamina, A. Schillert, S. Coassin, J.C. Bis, L. Broer, D.C. Crawford, N. Franceschini, R. Frikke-Schmidt, M. Haun, S. Holewijn, J.E. Huffman, S.J. Hwang, S. Kiechl, B. KolleritsM.E. Montasser, I.M. Nolte, M.E. Rudock, A. Senft, A. Teumer, P. van der Harst, V. Vitart, L.L. Waite, A.R. Wood, C.L. Wassel, D.M. Absher, M.A. Allison, N. Amin, A. Arnold, F.W. Asselbergs, Y. Aulchenko, S. Bandinelli, M. Barbalic, M. Boban, K. Brown-Gentry, D.J. Couper, M.H. Criqui, A. Dehghan, M. den Heijer, B. Dieplinger, J.Z. Ding, M. Dorr, C. Espinola-Klein, S.B. Felix, L. Ferrucci, A.R. Folsom, G. Fraedrich, Q. Gibson, R. Goodloe, G. Gunjaca, M. Haltmayer, G. Heiss, A. Hofman, A. Kieback, L.A. Kiemeney, I. Kolcic, I.J. Kullo, S.B. Kritchevsky, K.J. Lackner, X.H. Li, W.G. Lieb, K. Lohman, C. Meisinger, D. Melzer, E.R. Mohler, I. Mudnic, T. Mueller, G. Navis, F. Oberhollenzer, J.W. Olin, J. O'Connell, C.J. O'Donnell, W. Palmas, B.W.J.H. Penninx, A. Petersmann, O. Polasek, B.M. Psaty, B. Rantner, K. Rice, F. Rivadeneira, J.I. Rotter, A. Seldenrijk, M. Stadler, M. Summerer, T. Tanaka, A. Tybjaerg-Hansen, A. G. Uitterlinden, W.H. van Gilst, S.H. Vermeulen, S.H. Wild, P.S. Wild, J. Willeit, T. Zeller, T. Zemunik

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    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. Methods and 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. © 2012 American Heart Association, Inc.
    Original languageEnglish
    Pages (from-to)100-112
    JournalCirculation: Cardiovascular genetics
    Issue number1
    Publication statusPublished - 2012


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