Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies.
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.
Murabito, JM; White, CC; Kavousi, M; Sun, YV; Feitosa, MF; Nambi, V; Lamina, C; Schillert, A; Coassin, S; Bis, JC; Broer, L; Crawford, DC; Franceschini, N; Frikke-Schmidt, R; Haun, M; Holewijn, S; Huffman, JE; Hwang, S-J; Kiechl, S; Kollerits, B; Montasser, ME; Nolte, IM; Rudock, ME; Senft, A; Teumer, A; van der Harst, P; Vitart, V; Waite, LL; Wood, AR; Wassel, CL; Absher, DM; Allison, MA; Amin, N; Arnold, A; Asselbergs, FW; Aulchenko, Y; Bandinelli, S; Barbalic, M; Boban, M; Brown-Gentry, K; Couper, DJ; Criqui, MH; Dehghan, A; den Heijer, M; Dieplinger, B; Ding, J; Dörr, M; Espinola-Klein, C; Felix, SB; Ferrucci, L; Folsom, AR; Fraedrich, G; Gibson, Q; Goodloe, R; Gunjaca, G; Haltmayer, M; Heiss, G; Hofman, A; Kieback, A; Kiemeney, LA; Kolcic, I; Kullo, IJ; Kritchevsky, SB; Lackner, KJ; Li, X; Lieb, W; Lohman, K; Meisinger, C; Melzer, D; Mohler, ER; Mudnic, I; Mueller, T; Navis, G; Oberhollenzer, F; Olin, JW; O'Connell, J; O'Donnell, CJ; Palmas, W; Penninx, BW; Petersmann, A; Polasek, O; Psaty, BM; Rantner, B; Rice, K; Rivadeneira, F; Rotter, JI; Seldenrijk, A; Stadler, M; Summerer, M; Tanaka, T; Tybjaerg-Hansen, A; Uitterlinden, AG; van Gilst, WH; Vermeulen, SH; Wild, SH; Wild, PS; Willeit, J; Zeller, T; Zemunik, T; Zgaga, L; Assimes, TL; Blankenberg, S; Boerwinkle, E; Campbell, H; Cooke, JP; de Graaf, J; Herrington, D; Kardia, SLR; Mitchell, BD; Murray, A; Münzel, T; Newman, AB; Oostra, BA; Rudan, I; Shuldiner, AR; Snieder, H; van Duijn, CM; Völker, U; Wright, AF; Wichmann, H-E; Wilson, JF; Witteman, JCM; Liu, Y; Hayward, C; Borecki, IB; Ziegler, A; North, KE; Cupples, LA; Kronenberg, F
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