Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies
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Published:2012-02
Issue:1
Volume:5
Page:100-112
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ISSN:1942-325X
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Container-title:Circulation: Cardiovascular Genetics
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language:en
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Short-container-title:Circ Cardiovasc Genet
Author:
Murabito Joanne M.1, White Charles C.1, Kavousi Maryam1, Sun Yan V.1, Feitosa Mary F.1, Nambi Vijay1, Lamina Claudia1, Schillert Arne1, Coassin Stefan1, Bis Joshua C.1, Broer Linda1, Crawford Dana C.1, Franceschini Nora1, Frikke-Schmidt Ruth1, Haun Margot1, Holewijn Suzanne1, Huffman Jennifer E.1, Hwang Shih-Jen1, Kiechl Stefan1, Kollerits Barbara1, Montasser May E.1, Nolte Ilja M.1, Rudock Megan E.1, Senft Andrea1, Teumer Alexander1, van der Harst Pim1, Vitart Veronique1, Waite Lindsay L.1, Wood Andrew R.1, Wassel Christina L.1, Absher Devin M.1, Allison Matthew A.1, Amin Najaf1, Arnold Alice1, Asselbergs Folkert W.1, Aulchenko Yurii1, Bandinelli Stefania1, Barbalic Maja1, Boban Mladen1, Brown-Gentry Kristin1, Couper David J.1, Criqui Michael H.1, Dehghan Abbas1, den Heijer Martin1, Dieplinger Benjamin1, Ding Jingzhong1, Dörr Marcus1, Espinola-Klein Christine1, Felix Stephan B.1, Ferrucci Luigi1, Folsom Aaron R.1, Fraedrich Gustav1, Gibson Quince1, Goodloe Robert1, Gunjaca Grgo1, Haltmayer Meinhard1, Heiss Gerardo1, Hofman Albert1, Kieback Arne1, Kiemeney Lambertus A.1, Kolcic Ivana1, Kullo Iftikhar J.1, Kritchevsky Stephen B.1, Lackner Karl J.1, Li Xiaohui1, Lieb Wolfgang1, Lohman Kurt1, Meisinger Christa1, Melzer David1, Mohler Emile R.1, Mudnic Ivana1, Mueller Thomas1, Navis Gerjan1, Oberhollenzer Friedrich1, Olin Jeffrey W.1, O'Connell Jeff1, O'Donnell Christopher J.1, Palmas Walter1, Penninx Brenda W.1, Petersmann Astrid1, Polasek Ozren1, Psaty Bruce M.1, Rantner Barbara1, Rice Ken1, Rivadeneira Fernando1, Rotter Jerome I.1, Seldenrijk Adrie1, Stadler Marietta1, Summerer Monika1, Tanaka Toshiko1, Tybjaerg-Hansen Anne1, Uitterlinden Andre G.1, van Gilst Wiek H.1, Vermeulen Sita H.1, Wild Sarah H.1, Wild Philipp S.1, Willeit Johann1, Zeller Tanja1, Zemunik Tatijana1, Zgaga Lina1, Assimes Themistocles L.1, Blankenberg Stefan1, Boerwinkle Eric1, Campbell Harry1, Cooke John P.1, de Graaf Jacqueline1, Herrington David1, Kardia Sharon L.R.1, Mitchell Braxton D.1, Murray Anna1, Münzel Thomas1, Newman Anne B.1, Oostra Ben A.1, Rudan Igor1, Shuldiner Alan R.1, Snieder Harold1, van Duijn Cornelia M.1, Völker Uwe1, Wright Alan F.1, Wichmann H.-Erich1, Wilson James F.1, Witteman Jacqueline C.M.1, Liu Yongmei1, Hayward Caroline1, Borecki Ingrid B.1, Ziegler Andreas1, North Kari E.1, Cupples L. Adrienne1, Kronenberg Florian1
Affiliation:
1. A list of the institutions and affiliations for the authors of this report may be found in the Appendix at the end of this article.
Abstract
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Genetics(clinical),Cardiology and Cardiovascular Medicine,Genetics
Cited by
94 articles.
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