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 Jan 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

72 Citations (Scopus)

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

Fingerprint

Ankle Brachial Index
Genome-Wide Association Study
Peripheral Arterial Disease
Meta-Analysis
Chromosomes
Single Nucleotide Polymorphism
Coronary Artery Disease
Logistic Models
Genome
HapMap Project
Chromosomes, Human, Pair 9
Genetic Models
Population
Genes
Linear Models
Phenotype

Keywords

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

ASJC Scopus subject areas

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

Cite this

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

In: Circulation: Cardiovascular Genetics, Vol. 5, No. 1, 02.2012, p. 100-112.

Research output: Contribution to journalArticle

Murabito, 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, SJ, 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, Den Heijer, M, 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, HE, Wilson, JF, Witteman, JCM, Liu, Y, Hayward, C, Borecki, IB, Ziegler, A, North, KE, Cupples, LA & 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, vol. 5, no. 1, pp. 100-112. https://doi.org/10.1161/CIRCGENETICS.111.961292
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 Jan ; 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. / Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies. In: Circulation: Cardiovascular Genetics. 2012 ; Vol. 5, No. 1. pp. 100-112.
@article{2a5d745b1c854782bd1bfeb94a95fc5f,
title = "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 (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.",
keywords = "Cohort study, Genetic association, Genome-wide association study, Meta-analysis, Peripheral vascular disease",
author = "Murabito, {Joanne M.} and White, {Charles C.} and Maryam Kavousi and Sun, {Yan V.} and Feitosa, {Mary F.} and Vijay Nambi and Claudia Lamina and Arne Schillert and Stefan Coassin and Bis, {Joshua C.} and Linda Broer and Crawford, {Dana C.} and Nora Franceschini and Ruth Frikke-Schmidt and Margot Haun and Suzanne Holewijn and Huffman, {Jennifer E.} and Hwang, {Shih Jen} and Stefan Kiechl and Barbara Kollerits and Montasser, {May E.} and Nolte, {Ilja M.} and Rudock, {Megan E.} and Andrea Senft and Alexander Teumer and {Van Der Harst}, Pim and Veronique Vitart and Waite, {Lindsay L.} and Wood, {Andrew R.} and Wassel, {Christina L.} and Absher, {Devin M.} and Allison, {Matthew A.} and Najaf Amin and Alice Arnold and Asselbergs, {Folkert W.} and Yurii Aulchenko and Stefania Bandinelli and Maja Barbalic and Mladen Boban and Kristin Brown-Gentry and Couper, {David J.} and Criqui, {Michael H.} and Abbas Dehghan and {Den Heijer}, Martin and Benjamin Dieplinger and Jingzhong Ding and Marcus D{\"o}rr and Christine Espinola-Klein and Felix, {Stephan B.} and Luigi Ferrucci and Folsom, {Aaron R.} and Gustav Fraedrich and Quince Gibson and Robert Goodloe and Grgo Gunjaca and Meinhard Haltmayer and Gerardo Heiss and Albert Hofman and Arne Kieback and Kiemeney, {Lambertus A.} and Ivana Kolcic and Kullo, {Iftikhar Jan} and Kritchevsky, {Stephen B.} and Lackner, {Karl J.} and Xiaohui Li and Wolfgang Lieb and Kurt Lohman and Christa Meisinger and David Melzer and Mohler, {Emile R.} and Ivana Mudnic and Thomas Mueller and Gerjan Navis and Friedrich Oberhollenzer and Olin, {Jeffrey W.} and Jeff O'Connell and O'Donnell, {Christopher J.} and Walter Palmas and Penninx, {Brenda W.} and Astrid Petersmann and Ozren Polasek and Psaty, {Bruce M.} and Barbara Rantner and Ken Rice and Fernando Rivadeneira and Rotter, {Jerome I.} and Adrie Seldenrijk and Marietta Stadler and Monika Summerer and Toshiko Tanaka and Anne Tybjaerg-Hansen and Uitterlinden, {Andre G.} and {Van Gilst}, {Wiek H.} and Vermeulen, {Sita H.} and Wild, {Sarah H.} and Wild, {Philipp S.} and Johann Willeit and Tanja Zeller and Tatijana Zemunik and Lina Zgaga and Assimes, {Themistocles L.} and Stefan Blankenberg and Eric Boerwinkle and Harry Campbell and Cooke, {John P.} and {De Graaf}, Jacqueline and David Herrington and Kardia, {Sharon L R} and Mitchell, {Braxton D.} and Anna Murray and Thomas M{\"u}nzel and Newman, {Anne B.} and Oostra, {Ben A.} and Igor Rudan and Shuldiner, {Alan R.} and Harold Snieder and {Van Duijn}, {Cornelia M.} and Uwe V{\"o}lker and Wright, {Alan F.} and Wichmann, {H. Erich} and Wilson, {James F.} and Witteman, {Jacqueline C M} and Yongmei Liu and Caroline Hayward and Borecki, {Ingrid B.} and Andreas Ziegler and North, {Kari E.} and Cupples, {L. Adrienne} and Florian Kronenberg",
year = "2012",
month = "2",
doi = "10.1161/CIRCGENETICS.111.961292",
language = "English (US)",
volume = "5",
pages = "100--112",
journal = "Circulation. Genomic and precision medicine",
issn = "1942-325X",
publisher = "Lippincott Williams and Wilkins Ltd.",
number = "1",

}

TY - JOUR

T1 - Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies

AU - Murabito, Joanne M.

AU - White, Charles C.

AU - Kavousi, Maryam

AU - Sun, Yan V.

AU - Feitosa, Mary F.

AU - Nambi, Vijay

AU - Lamina, Claudia

AU - Schillert, Arne

AU - Coassin, Stefan

AU - Bis, Joshua C.

AU - Broer, Linda

AU - Crawford, Dana C.

AU - Franceschini, Nora

AU - Frikke-Schmidt, Ruth

AU - Haun, Margot

AU - Holewijn, Suzanne

AU - Huffman, Jennifer E.

AU - Hwang, Shih Jen

AU - Kiechl, Stefan

AU - Kollerits, Barbara

AU - Montasser, May E.

AU - Nolte, Ilja M.

AU - Rudock, Megan E.

AU - Senft, Andrea

AU - Teumer, Alexander

AU - Van Der Harst, Pim

AU - Vitart, Veronique

AU - Waite, Lindsay L.

AU - Wood, Andrew R.

AU - Wassel, Christina L.

AU - Absher, Devin M.

AU - Allison, Matthew A.

AU - Amin, Najaf

AU - Arnold, Alice

AU - Asselbergs, Folkert W.

AU - Aulchenko, Yurii

AU - Bandinelli, Stefania

AU - Barbalic, Maja

AU - Boban, Mladen

AU - Brown-Gentry, Kristin

AU - Couper, David J.

AU - Criqui, Michael H.

AU - Dehghan, Abbas

AU - Den Heijer, Martin

AU - Dieplinger, Benjamin

AU - Ding, Jingzhong

AU - Dörr, Marcus

AU - Espinola-Klein, Christine

AU - Felix, Stephan B.

AU - Ferrucci, Luigi

AU - Folsom, Aaron R.

AU - Fraedrich, Gustav

AU - Gibson, Quince

AU - Goodloe, Robert

AU - Gunjaca, Grgo

AU - Haltmayer, Meinhard

AU - Heiss, Gerardo

AU - Hofman, Albert

AU - Kieback, Arne

AU - Kiemeney, Lambertus A.

AU - Kolcic, Ivana

AU - Kullo, Iftikhar Jan

AU - Kritchevsky, Stephen B.

AU - Lackner, Karl J.

AU - Li, Xiaohui

AU - Lieb, Wolfgang

AU - Lohman, Kurt

AU - Meisinger, Christa

AU - Melzer, David

AU - Mohler, Emile R.

AU - Mudnic, Ivana

AU - Mueller, Thomas

AU - Navis, Gerjan

AU - Oberhollenzer, Friedrich

AU - Olin, Jeffrey W.

AU - O'Connell, Jeff

AU - O'Donnell, Christopher J.

AU - Palmas, Walter

AU - Penninx, Brenda W.

AU - Petersmann, Astrid

AU - Polasek, Ozren

AU - Psaty, Bruce M.

AU - Rantner, Barbara

AU - Rice, Ken

AU - Rivadeneira, Fernando

AU - Rotter, Jerome I.

AU - Seldenrijk, Adrie

AU - Stadler, Marietta

AU - Summerer, Monika

AU - Tanaka, Toshiko

AU - Tybjaerg-Hansen, Anne

AU - Uitterlinden, Andre G.

AU - Van Gilst, Wiek H.

AU - Vermeulen, Sita H.

AU - Wild, Sarah H.

AU - Wild, Philipp S.

AU - Willeit, Johann

AU - Zeller, Tanja

AU - Zemunik, Tatijana

AU - Zgaga, Lina

AU - Assimes, Themistocles L.

AU - Blankenberg, Stefan

AU - Boerwinkle, Eric

AU - Campbell, Harry

AU - Cooke, John P.

AU - De Graaf, Jacqueline

AU - Herrington, David

AU - Kardia, Sharon L R

AU - Mitchell, Braxton D.

AU - Murray, Anna

AU - Münzel, Thomas

AU - Newman, Anne B.

AU - Oostra, Ben A.

AU - Rudan, Igor

AU - Shuldiner, Alan R.

AU - Snieder, Harold

AU - Van Duijn, Cornelia M.

AU - Völker, Uwe

AU - Wright, Alan F.

AU - Wichmann, H. Erich

AU - Wilson, James F.

AU - Witteman, Jacqueline C M

AU - Liu, Yongmei

AU - Hayward, Caroline

AU - Borecki, Ingrid B.

AU - Ziegler, Andreas

AU - North, Kari E.

AU - Cupples, L. Adrienne

AU - Kronenberg, Florian

PY - 2012/2

Y1 - 2012/2

N2 - 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.

AB - 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.

KW - Cohort study

KW - Genetic association

KW - Genome-wide association study

KW - Meta-analysis

KW - Peripheral vascular disease

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