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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.

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 (?=-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.

SUBMITTER: Murabito JM 

PROVIDER: S-EPMC3303225 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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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.

Murabito Joanne M JM   White Charles C CC   Kavousi Maryam M   Sun Yan V YV   Feitosa Mary F MF   Nambi Vijay V   Lamina Claudia C   Schillert Arne A   Coassin Stefan S   Bis Joshua C JC   Broer Linda L   Crawford Dana C DC   Franceschini Nora N   Frikke-Schmidt Ruth R   Haun Margot M   Holewijn Suzanne S   Huffman Jennifer E JE   Hwang Shih-Jen SJ   Kiechl Stefan S   Kollerits Barbara B   Montasser May E ME   Nolte Ilja M IM   Rudock Megan E ME   Senft Andrea A   Teumer Alexander A   van der Harst Pim P   Vitart Veronique V   Waite Lindsay L LL   Wood Andrew R AR   Wassel Christina L CL   Absher Devin M DM   Allison Matthew A MA   Amin Najaf N   Arnold Alice A   Asselbergs Folkert W FW   Aulchenko Yurii Y   Bandinelli Stefania S   Barbalic Maja M   Boban Mladen M   Brown-Gentry Kristin K   Couper David J DJ   Criqui Michael H MH   Dehghan Abbas A   den Heijer Martin M   Dieplinger Benjamin B   Ding Jingzhong J   Dörr Marcus M   Espinola-Klein Christine C   Felix Stephan B SB   Ferrucci Luigi L   Folsom Aaron R AR   Fraedrich Gustav G   Gibson Quince Q   Goodloe Robert R   Gunjaca Grgo G   Haltmayer Meinhard M   Heiss Gerardo G   Hofman Albert A   Kieback Arne A   Kiemeney Lambertus A LA   Kolcic Ivana I   Kullo Iftikhar J IJ   Kritchevsky Stephen B SB   Lackner Karl J KJ   Li Xiaohui X   Lieb Wolfgang W   Lohman Kurt K   Meisinger Christa C   Melzer David D   Mohler Emile R ER   Mudnic Ivana I   Mueller Thomas T   Navis Gerjan G   Oberhollenzer Friedrich F   Olin Jeffrey W JW   O'Connell Jeff J   O'Donnell Christopher J CJ   Palmas Walter W   Penninx Brenda W BW   Petersmann Astrid A   Polasek Ozren O   Psaty Bruce M BM   Rantner Barbara B   Rice Ken K   Rivadeneira Fernando F   Rotter Jerome I JI   Seldenrijk Adrie A   Stadler Marietta M   Summerer Monika M   Tanaka Toshiko T   Tybjaerg-Hansen Anne A   Uitterlinden Andre G AG   van Gilst Wiek H WH   Vermeulen Sita H SH   Wild Sarah H SH   Wild Philipp S PS   Willeit Johann J   Zeller Tanja T   Zemunik Tatijana T   Zgaga Lina L   Assimes Themistocles L TL   Blankenberg Stefan S   Boerwinkle Eric E   Campbell Harry H   Cooke John P JP   de Graaf Jacqueline J   Herrington David D   Kardia Sharon L R SL   Mitchell Braxton D BD   Murray Anna A   Münzel Thomas T   Newman Anne B AB   Oostra Ben A BA   Rudan Igor I   Shuldiner Alan R AR   Snieder Harold H   van Duijn Cornelia M CM   Völker Uwe U   Wright Alan F AF   Wichmann H-Erich HE   Wilson James F JF   Witteman Jacqueline C M JC   Liu Yongmei Y   Hayward Caroline C   Borecki Ingrid B IB   Ziegler Andreas A   North Kari E KE   Cupples L Adrienne LA   Kronenberg Florian F  

Circulation. Cardiovascular genetics 20111223 1

<h4>Background</h4>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.<h4>Methods and results</h4>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 nuc  ...[more]

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