EXPEDITED PUBLICATON
Lack of Association Between the Trp719Arg Polymorphism in Kinesin-Like Protein-6 and Coronary Artery Disease in 19 Case-Control Studies
Themistocles L. Assimes, MD, PhD1,*,
Hilma Hólm, MD2,
Sekar Kathiresan, MD3,4,5,6,
Muredach P. Reilly, MB7,8,
Gudmar Thorleifsson, PhD2,
Benjamin F. Voight, PhD4,5,9,
Jeanette Erdmann, PhD10,
Christina Willenborg, MSc10,11,
Dhananjay Vaidya, MBBS, PhD, MPH12,
Changchun Xie, PhD13,
Chris C. Patterson, PhD14,
Thomas M. Morgan, MD15,
Mary Susan Burnett, PhD16,
Mingyao Li, PhD17,
Mark A. Hlatky, MD1,
Joshua W. Knowles, MD, PhD1,
John R. Thompson, PhD18,
Devin Absher, PhD19,
Carlos Iribarren, MD, MPH, PhD20,
Alan Go, MD20,
Stephen P. Fortmann, MD1,
Stephen Sidney, MD, MPH20,
Neil Risch, PhD21,
Hua Tang, PhD22,
Richard M. Myers, PhD19,
Klaus Berger, MD23,
Monika Stoll, PhD24,
Svati H. Shah, MD, MHS25,
Gudmundur Thorgeirsson, MD, PhD26,27,
Karl Andersen, MD, PhD26,27,
Aki S. Havulinna, MSc28,
J. Enrique Herrera, MS12,
Nauder Faraday, MD29,
Yoonhee Kim, PhD30,
Brian G. Kral, MD, MPH12,
Rasika A. Mathias, ScD12,
Ingo Ruczinski, PhD31,
Bhoom Suktitipat, MD32,
Alexander F. Wilson, PhD30,
Lisa R. Yanek, MPH12,
Lewis C. Becker, MD12,
Patrick Linsel-Nitschke, MD10,
Wolfgang Lieb, MD10,
Inke R. König, PhD11,
Christian Hengstenberg, MD33,
Marcus Fischer, MD33,
Klaus Stark, PhD33,
Wibke Reinhard, MD33,
Janina Winogradow, MD33,
Martina Grassl, MD33,
Anika Grosshennig, MSc10,11,
Michael Preuss, MSc10,11,
Stefan Schreiber, MD34,
H.-Erich Wichmann, MD35,36,37,
Christa Meisinger, MD, MPH35,38,
Jean Yee, BS39,40,
Yechiel Friedlander, PhD41,
Ron Do, MSc42,
James B. Meigs, MD, MPH6,43,
Gordon Williams, MD6,44,
David M. Nathan, MD6,45,
Calum A. MacRae, MD, PhD3,6,
Liming Qu, MS17,
Robert L. Wilensky, MD7,8,
William H. Matthai, Jr, MD7,
Atif N. Qasim, MD8,
Hakon Hakonarson, MD, PhD46,
Augusto D. Pichard, MD16,
Kenneth M. Kent, MD, PhD16,
Lowell Satler, MD16,
Joseph M. Lindsay, MD16,
Ron Waksman, MD1,6,
Christopher W. Knouff, MD, PhD47,
Dawn M. Waterworth, PhD47,
Max C. Walker, BSc47,
Vincent E. Mooser, MD47,
Jaume Marrugat, MD, PhD48,
Gavin Lucas, PhD48,
Isaac Subirana, MSc48,
Joan Sala, MD49,
Rafael Ramos, MD, PhD50,
Nicola Martinelli, MD51,
Oliviero Olivieri, MD51,
Elisabetta Trabetti, PhD52,
Giovanni Malerba, PhD52,
Pier Franco Pignatti, MD52,
Candace Guiducci, BS5,
Daniel Mirel, PhD5,
Melissa Parkin, BS5,
Joel N. Hirschhorn, MD, PhD5,53,
Rosanna Asselta, PhD54,
Stefano Duga, PhD54,
Kiran Musunuru, MD, PhD, MPH3,4,5,6,
Mark J. Daly, PhD4,5,6,
Shaun Purcell, PhD4,5,55,
Sandra Eifert, MD56,
Peter S. Braund, MSc57,
Benjamin J. Wright, PhD18,
Anthony J. Balmforth, PhD58,
Stephen G. Ball, PhD58 Myocardial Infarction Genetics Consortium Wellcome Trust Case Control Consortium, Cardiogenics,
Willem H. Ouwehand, MD, PhD59,60,
Panos Deloukas, PhD60,
Michael Scholz61,
Francois Cambien, MD62,
Andreas Huge, PhD24,
Thomas Scheffold, PhD63,
Veikko Salomaa, MD, PhD28,
Domenico Girelli, MD, PhD51,
Christopher B. Granger, MD64,
Leena Peltonen, MD, PhD5,60,65,
Pascal P. McKeown, MD14,
David Altshuler, MD, PhD4,5,6,9,53,
Olle Melander, MD, PhD66,
Joseph M. Devaney, PhD16,
Stephen E. Epstein, MD16,
Daniel J. Rader, MD8,9,
Roberto Elosua, MD, PhD48,
James C. Engert, PhD42,67,
Sonia S. Anand, MD, PhD13,
Alistair S. Hall, MD58,
Andreas Ziegler, PhD11,
Christopher J. O'Donnell, MD, MPH3,6,68,
John A. Spertus, MD, MPh69,
David Siscovick, MD, MPH39,
Stephen M. Schwartz, PhD39,40,
Diane Becker, MPH, ScD12,
Unnur Thorsteinsdottir, PhD2,26,
Kari Stefansson, MD, PhD2,26,
Heribert Schunkert, MD10,
Nilesh J. Samani, MD57,
Thomas Quertermous, MD1
1 Department of Medicine, Stanford University School of Medicine, Stanford, California
2 deCODE Genetics, Reykjavik, Iceland
3 Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts
4 Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
5 Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
6 Department of Medicine, Harvard Medical School, Boston, Massachusetts
7 The Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania
8 The Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
9 Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
10 Medizinische Klinik II, Universität zu Lübeck, Lübeck, Germany
11 Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany
12 Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland
13 Population Health Research Institute, Hamilton Health Sciences and Departments of Medicine and Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
14 Centre for Public Health, Queen's University Belfast, Institute of Clinical Science, Belfast, Northern Ireland, United Kingdom
15 Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee
16 Cardiovascular Research Institute, MedStar Health Research Institute, Washington Hospital Center, Washington, DC
17 Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania
18 Department of Health Sciences, University of Leicester, Leicester, United Kingdom
19 HudsonAlpha Institute for Biotechnology, Huntsville, Alabama
20 Division of Research, Kaiser Permanente, Oakland, California
21 Institute for Human Genetics, University of California, San Francisco, San Francisco, California
22 Department of Genetics, Stanford University School of Medicine, Stanford, California
23 Institute of Epidemiology and Social Medicine, University Münster, Münster, Germany
24 Leibniz-Institute for Arteriosclerosis Research, University Münster, Münster, Germany
25 Department of Medicine and Center for Human Genetics, Duke University Medical Center, Durham, North Carolina
26 Faculty of Medicine, University of Iceland, Reykjav k, Iceland
27 Department of Medicine, Landspitali University Hospital, Reykjavk, Iceland
28 Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
29 Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
30 Genometrics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland
31 Department of Biostatistics, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
32 Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
33 Klinik und Poliklinik für Innere Medizin II,Universität Regensburg, Regensburg, Germany
34 Institut für Klinische Molekularbiologie, Christian-Albrechts Universität, Kiel, Germany
35 Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
36 Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität Munich, Munich, Germany
37 Klinikum Grosshadern, Munich, Germany
38 Klinikum Augsburg, KORA Myocardial Infarction Registry, Augsburg, Germany
39 Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington
40 Department of Epidemiology, University of Washington, Seattle, Washington
41 Unit of Epidemiology, Hebrew University-Hadassah School of Public Health, Jerusalem, Israel
42 Department of Human Genetics, McGill University, Montréal, Québec, Canada
43 General Medicine Division, Department of Medicine, Massachusetts General Hospital, Boston, Maryland
44 Cardiovascular Endocrinology Section, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, Maryland
45 Diabetes Center, Massachusetts General Hospital, Boston, Maryland
46 The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylania
47 Genetics Division and Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylania
48 Cardiovascular Epidemiology and Genetics, IMIM, and CIBER Epidemiología y Salud Pública, Barcelona, Spain
49 Servei de Cardiologia i Unitat Coronària, Hospital de Girona Josep Trueta and Institut de Investigació Biomèdica de Girona, Girona, Spain
50 Research Unit, Family Medicine, Girona. Jordi Gol Institute for Primary Care Research (IDIAP Jordi Gol) and Primary Care Services, Girona. Catalan Institute of Health (ICS), Catalunya, Spain; Department of Medical Sciences, School of Medicine, University of Girona, Spain
51 Department of Medicine, University of Verona, Verona, Italy
52 Department of Life and Reproduction Sciences, Section of Biology and Genetics, University of Verona, Verona, Italy
53 Department of Genetics, Harvard Medical School, Boston, Maryland
54 Dipartimento di Biologia e Genetica per le Scienze Mediche, Università degli Studi di Milano, Milan, Italy
55 Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Maryland
56 Herzchirurgische Klinik und Poliklinik der Ludwig-Maximilian-Universität München, München, Germany
57 Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, United Kingdom
58 Multidisciplinary Cardiovascular Research Centre (MCRC), Leeds Institute of Genetics Health and Therapeutics (LIGHT), University of Leeds, Leeds, United Kingdom
59 Department of Haematology, University of Cambridge and NHS Blood and Transplant, Long Road, Cambridge, United Kingdom
60 Wellcome Trust Sanger Institute, Cambridge, United Kingdom
61 Trium Analysis Online GmbH, Munich, Germany
62 INSERM UMRS 936, Universite Pierre et Marie Curie–Paris, Paris, France
63 Institute for Heart and Circulation Research of the University of Witten/Herdecke, Dortmund, Germany
64 Department of Medicine and Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina
65 Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
66 Department of Clinical Sciences, Hypertension and Cardiovascular Diseases, University Hospital Malmö, Lund University, Malmö, Sweden
67 Department of Medicine, McGill University, Montreal, Quebec, Canada
68 National, Heart, Lung, and Blood Institute and its Framingham Heart Study, Framingham, Massachusetts
69 Mid-America Heart Institute and University of Missouri-Kansas City, Kansas City, Missouri
Manuscript received November 28, 2009;
revised manuscript received June 14, 2010,
accepted June 22, 2010.
* Reprint requests and correspondence: Dr. Themistocles L. Assimes, Population Health Sciences Building, Stanford University School of Medicine, Stanford, California 94304-1334 (Email: tassimes{at}stanford.edu).
Objectives: We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD).
Background: Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers.
Methods: The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports.
Results: A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of  2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls as well as all non-European subgroups.
Conclusions: The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study.
Key Words: coronary artery disease • KIF6 • kinesin-like protein 6 • myocardial infarction • polymorphism
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Abbreviations and Acronyms
| | CAD = coronary artery disease | | CI = confidence interval | | HR = hazard ratio | | MI = myocardial infarction | | OR = odds ratio | | SNP = single nucleotide polymorphism |
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