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

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

Research output: Contribution to journalArticle

76 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)100-112
Number of pages13
JournalCirculation: Cardiovascular Genetics
Volume5
Issue number1
DOIs
StatePublished - Feb 2012

Keywords

  • Cohort study
  • Genetic association
  • Genome-wide association study
  • Meta-analysis
  • Peripheral vascular disease

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

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    Murabito, J. M., White, C. C., Kavousi, M., Sun, Y. V., Feitosa, M. F., Nambi, V., Lamina, C., Schillert, A., Coassin, S., Bis, J. C., Broer, L., Crawford, D. C., Franceschini, N., Frikke-Schmidt, R., Haun, M., Holewijn, S., Huffman, J. E., Hwang, S. J., Kiechl, S., ... Kronenberg, F. (2012). Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies. Circulation: Cardiovascular Genetics, 5(1), 100-112. https://doi.org/10.1161/CIRCGENETICS.111.961292