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Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies.

Tuesday,2012-11-06 12:26 America/Los_Angeles — eenright
TitleAssociation between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies.
Publication TypeJournal Article
Year of Publication2012
AuthorsMurabito, 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, Heijer, Mden, 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, AL, Kronenberg, F
JournalCirc Cardiovasc Genet
Volume5
Issue1
Pagination100-12
Date Published2012 Feb 01
ISSN1942-3268
KeywordsAdult, Age Factors, Aged, Aged, 80 and over, Alleles, Ankle Brachial Index, Chromosomes, Human, Pair 9, Cohort Studies, Cyclin-Dependent Kinase Inhibitor p15, Female, Genome-Wide Association Study, Genotype, HapMap Project, Humans, Logistic Models, Male, Middle Aged, Peripheral Vascular Diseases, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Sex Factors
Abstract<p><b>BACKGROUND: </b>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.</p><p><b>METHODS AND RESULTS: </b>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).</p><p><b>CONCLUSIONS: </b>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.</p>
DOI10.1161/CIRCGENETICS.111.961292
Alternate JournalCirc Cardiovasc Genet
PubMed ID22199011
PubMed Central IDPMC3303225
Grant ListM01-RR00425 / RR / NCRR NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
N01 HC-95169 / HC / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
HL08770002 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
CZB/4/710 / / Chief Scientist Office / United Kingdom
HHSN268201100009I / HL / NHLBI NIH HHS / United States
N01-AG-12111 / AG / NIA NIH HHS / United States
R01 HL075366 / HL / NHLBI NIH HHS / United States
N01 HC-95165 / HC / NHLBI NIH HHS / United States
R01 AR046838 / AR / NIAMS NIH HHS / United States
N1AG62101A / AG / NIA NIH HHS / United States
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R01 HL059367-11 / HL / NHLBI NIH HHS / United States
R01 MH081802 / MH / NIMH NIH HHS / United States
N01HC95160 / HL / NHLBI NIH HHS / United States
UL1 RR024156-06 / RR / NCRR NIH HHS / United States
P30 DK072488-03 / DK / NIDDK NIH HHS / United States
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MC_U127561128 / / Medical Research Council / United Kingdom
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N01HC75150 / HL / NHLBI NIH HHS / United States
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HHSN268201100009C / HL / NHLBI NIH HHS / United States
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HHSN268201100005C / HL / NHLBI NIH HHS / United States
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R01 DK068336-03 / DK / NIDDK NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
R01 HL075774 / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
N01-HC-85079 / HC / NHLBI NIH HHS / United States
1K12 HL087746 / HL / NHLBI NIH HHS / United States
AR046838 / AR / NIAMS NIH HHS / United States
T32 AG000219 / AG / NIA NIH HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
N01-HC-85239 / HC / NHLBI NIH HHS / United States
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R69/0208 / / The Dunhill Medical Trust / United Kingdom
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R01 HL088119 / HL / NHLBI NIH HHS / United States
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