Edinburgh Research Explorer 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.

Robert J. Goodloe | May E. Montasser | S. Bandinelli | D. Absher | T. Assimes | L. Kiemeney | E. Boerwinkle | A. Folsom | D. Couper | A. Dehghan | F. Rivadeneira | W. Lieb | B. Penninx | H. Snieder | C. Meisinger | P. Harst | S. Coassin | M. Criqui | I. Rudan | S. Kiechl | F. Oberhollenzer | M. Heijer | I. Kullo | A. Petersmann | D. Crawford | J. Bis | N. Amin | I. Kolčić | O. Polašek | V. Vitart | M. Feitosa | N. Franceschini | I. Nolte | Jingzhong Ding | J. O'connell | W. Palmas | A. Shuldiner | B. Mitchell | E. Mohler | A. Wood | K. Brown-Gentry | M. Kavousi | C. Duijn | M. Dörr | G. Fraedrich | B. Rantner | Q. Gibson | L. Zgaga | A. Arnold | M. Allison | L. Broer | R. Frikke-Schmidt | C. Lamina | T. Zeller | P. Wild | A. Schillert | K. Lackner | T. Münzel | W. H. Gilst | B. Dieplinger | M. Haltmayer | J. Graaf | S. Holewijn | T. Zemunik | J. Huffman | M. Boban | M. Rudock | M. Haun | B. Kollerits | J. Olin | C. Wassel | I. Mudnić | M. Summerer | Mueller | M. Stadler | H. Sita | Alexander | Yan V. Sun | A. Kieback | A. Seldenrijk | Xiaohui Li | V. Nambi | Harry Campbell | Thomas | Xiaohui Li | Kenneth M. Rice | David | Hansen | Anna | Teumer | C. O’Donnell | U. Völker | Y. Aulchenko | Andrea Senft | Willeit | Anne Newman | A. Uitterlinden | Toshiko Tanaka | B. Oostra | B. Psaty | S. Kardia | Stephan B. Felix | W. Folkert | Asselbergs | Jingzhong Ding | Charles White | Stephen B Kritchevsky | Gerardo Heiss | Albert Hofman | Gerjan Navis | Stefan Blankenberg | Sarah H. Wild | Shih-Jen | Hwang | L. Lindsay | Waite | Alice Arnold | Maja | Barbalić | Christine | Espinola-Klein | Luigi Ferrucci | Grgo | Gunjaca | Mstat Kurt Lohman | David Melzer | Jerome I. Rotter | -. AnneTybjaerg | Vermeulen | Johann | John P. Cooke | Herrington | Murray | Alan F. Wright | Yan V. Sun | Shih-Jen | Hwang | L. Lindsay | Maja | Christine | Grgo | Gunjaca | Mstat Kurt Lohman | -. AnneTybjaerg | Vermeulen | Johann

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