Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies
Authors: Murabito Joanne M. , White Charles C. , Kavousi Maryam , Sun Yan V. , Feitosa Mary F. , Nambi Vijay , Lamina Claudia , Schillert Arne , Coassin Stefan , Bis Joshua C. , Broer Linda , Crawford Dana C. , Franceschini Nora , Frikke-Schmidt Ruth , Haun Margot , Holewijn Suzanne , Huffman Jennifer E. , Hwang Shih-Jen , Kiechl Stefan , Kollerits Barbara , Montasser May E. , Nolte Ilja M. , Rudock Megan E. , Senft Andrea , Teumer Alexander , van der Harst Pim , Vitart Veronique , Waite Lindsay L. , Wood Andrew R. , Wassel Christina L. , Absher Devin M. , Allison Matthew A. , Amin Najaf , Arnold Alice , Asselbergs Folkert W. , Aulchenko Yurii , Bandinelli Stefania , Barbalic Maja , Boban Mladen , Brown-Gentry Kristin , Couper David J. , Criqui Michael H. , Dehghan Abbas , den Heijer Martin , Dieplinger Benjamin , Ding Jingzhong , Dörr Marcus , Espinola-Klein Christine , Felix Stephan B. , Ferrucci Luigi , Folsom Aaron R. , Fraedrich Gustav , Gibson Quince , Goodloe Robert , Gunjaca Grgo , Haltmayer Meinhard , Heiss Gerardo , Hofman Albert , Kieback Arne , Kiemeney Lambertus A. , Kolcic Ivana , Kullo Iftikhar J. , Kritchevsky Stephen B. , Lackner Karl J. , Li Xiaohui , Lieb Wolfgang , Lohman Kurt , Meisinger Christa , Melzer David , Mohler Emile R. , Mudnic Ivana , Mueller Thomas , Navis Gerjan , Oberhollenzer Friedrich , Olin Jeffrey W. , O'Connell Jeff , O'Donnell Christopher J. , Palmas Walter , Penninx Brenda W. , Petersmann Astrid , Polasek Ozren , Psaty Bruce M. , Rantner Barbara , Rice Ken , Rivadeneira Fernando , Rotter Jerome I. , Seldenrijk Adrie , Stadler Marietta , Summerer Monika , Tanaka Toshiko , Tybjaerg-Hansen Anne , Uitterlinden Andre G. , van Gilst Wiek H. , Vermeulen Sita H. , Wild Sarah H. , Wild Philipp S. , Willeit Johann , Zeller Tanja , Zemunik Tatijana , Zgaga Lina , Assimes Themistocles L. , Blankenberg Stefan , Boerwinkle Eric , Campbell Harry , Cooke John P. , de Graaf Jacqueline , Herrington David , Kardia Sharon L.R. , Mitchell Braxton D. , Murray Anna , Münzel Thomas , Newman Anne B. , Oostra Ben A. , Rudan Igor , Shuldiner Alan R. , Snieder Harold , van Duijn Cornelia M. , Völker Uwe , Wright Alan F. , Wichmann H.-Erich , Wilson James F. , Witteman Jacqueline C.M. , Liu Yongmei , Hayward Caroline , Borecki Ingrid B. , Ziegler Andreas , North Kari E. , Cupples L. Adrienne , Kronenberg Florian 
Published: December 2011

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.