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Research Article

Homocysteine and Coronary Heart Disease: Meta-analysis of MTHFR Case-Control Studies, Avoiding Publication Bias

  • Robert Clarke equal contributor mail,

    equal contributor Contributed equally to this work with: Robert Clarke, Derrick A. Bennett, Sarah Parish, Rory Collins, Richard Peto

    Robert.Clarke@ctsu.ox.ac.uk

    Affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, United Kingdom

    X
  • Derrick A. Bennett equal contributor,

    equal contributor Contributed equally to this work with: Robert Clarke, Derrick A. Bennett, Sarah Parish, Rory Collins, Richard Peto

    Affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, United Kingdom

    X
  • Sarah Parish equal contributor,

    equal contributor Contributed equally to this work with: Robert Clarke, Derrick A. Bennett, Sarah Parish, Rory Collins, Richard Peto

    Affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, United Kingdom

    X
  • Petra Verhoef,

    Affiliation: Unilever Research and Development, Vlaardingen, The Netherlands

    X
  • Mariska Dötsch-Klerk,

    Affiliation: Unilever Research and Development, Vlaardingen, The Netherlands

    X
  • Mark Lathrop,

    Affiliation: Centre National de Genotypage, Evry, France

    X
  • Peng Xu,

    Affiliation: Centre National de Genotypage, Evry, France

    X
  • Børge G. Nordestgaard,

    Affiliation: Herlev Hospital Department of Clinical Biochemistry, University of Copenhagen, Copenhagen, Denmark

    X
  • Hilma Holm,

    Affiliation: deCODE Inc, Rejkavik, Iceland

    X
  • Jemma C. Hopewell,

    Affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, United Kingdom

    X
  • Danish Saleheen,

    Affiliations: Department of Public Health and Primary Care, University of Cambridge, United Kingdom, Center for Non-Communicable Diseases, Karachi, Pakistan

    X
  • Toshihiro Tanaka,

    Affiliation: RIKEN Centre for Genomic Medicine, Yokohama, Japan

    X
  • Sonia S. Anand,

    Affiliation: Population Health Research Institute, Hamilton, Canada

    X
  • John C. Chambers,

    Affiliation: Imperial College Faculty of Medicine, University of London, London, United Kingdom

    X
  • Marcus E. Kleber,

    Affiliation: Luric Study Non-Profit LCC, University of Freiburg, Freiburg, Germany

    X
  • Willem H. Ouwehand,

    Affiliation: Department of Haematology, University of Cambridge, United Kingdom

    X
  • Yoshiji Yamada,

    Affiliation: Mie University Life Science Research Center, Tsu, Japan

    X
  • Clara Elbers,

    Affiliation: Department of Medical Genetics, University of Utrecht, Utrecht, The Netherlands

    X
  • Bas Peters,

    Affiliation: Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, The Netherlands

    X
  • Alexandre F. R. Stewart,

    Affiliation: Heart Institute, University of Ottawa, Ottawa, Canada

    X
  • Muredach M. Reilly,

    Affiliation: Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America

    X
  • Barbara Thorand,

    Affiliation: Helmholtz Zentrum, Institute of Epidemiology II, German Research Center for Environmental Health, Munich, Germany

    X
  • Salim Yusuf,

    Affiliation: Population Health Research Institute, Hamilton, Canada

    X
  • James C. Engert,

    Affiliation: McGill University Health Centre, Montreal, Canada

    X
  • Themistocles L. Assimes,

    Affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America

    X
  • Jaspal Kooner,

    Affiliation: Imperial College Faculty of Medicine, University of London, London, United Kingdom

    X
  • John Danesh,

    Affiliation: Department of Public Health and Primary Care, University of Cambridge, United Kingdom

    X
  • Hugh Watkins,

    Affiliation: Department of Cardiovascular Medicine, University of Oxford, United Kingdom

    X
  • Nilesh J. Samani,

    Affiliation: Department of Cardiovascular Sciences, University of Leicester, United Kingdom

    X
  • Rory Collins equal contributor,

    equal contributor Contributed equally to this work with: Robert Clarke, Derrick A. Bennett, Sarah Parish, Rory Collins, Richard Peto

    Affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, United Kingdom

    X
  • Richard Peto equal contributor,

    equal contributor Contributed equally to this work with: Robert Clarke, Derrick A. Bennett, Sarah Parish, Rory Collins, Richard Peto

    Affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, United Kingdom

    X
  • for the MTHFR Studies Collaborative Group

    Membership of the MTHFR Studies Collaborative Group is provided in the Acknowledgments.

    X
  • Published: February 21, 2012
  • DOI: 10.1371/journal.pmed.1001177

About the Authors

Robert Clarke, Derrick A. Bennett, Sarah Parish, Jemma C. Hopewell, Rory Collins, Richard Peto
Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, United Kingdom
Petra Verhoef, Mariska Dötsch-Klerk
Unilever Research and Development, Vlaardingen, The Netherlands
Mark Lathrop, Peng Xu
Centre National de Genotypage, Evry, France
Børge G. Nordestgaard
Herlev Hospital Department of Clinical Biochemistry, University of Copenhagen, Copenhagen, Denmark
Hilma Holm
deCODE Inc, Rejkavik, Iceland
Danish Saleheen, John Danesh
Department of Public Health and Primary Care, University of Cambridge, United Kingdom
Danish Saleheen
Center for Non-Communicable Diseases, Karachi, Pakistan
Toshihiro Tanaka
RIKEN Centre for Genomic Medicine, Yokohama, Japan
Sonia S. Anand, Salim Yusuf
Population Health Research Institute, Hamilton, Canada
John C. Chambers, Jaspal Kooner
Imperial College Faculty of Medicine, University of London, London, United Kingdom
Marcus E. Kleber
Luric Study Non-Profit LCC, University of Freiburg, Freiburg, Germany
Willem H. Ouwehand
Department of Haematology, University of Cambridge, United Kingdom
Yoshiji Yamada
Mie University Life Science Research Center, Tsu, Japan
Clara Elbers
Department of Medical Genetics, University of Utrecht, Utrecht, The Netherlands
Bas Peters
Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, The Netherlands
Alexandre F. R. Stewart
Heart Institute, University of Ottawa, Ottawa, Canada
Muredach M. Reilly
Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
Barbara Thorand
Helmholtz Zentrum, Institute of Epidemiology II, German Research Center for Environmental Health, Munich, Germany
James C. Engert
McGill University Health Centre, Montreal, Canada
Themistocles L. Assimes
Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America
Hugh Watkins
Department of Cardiovascular Medicine, University of Oxford, United Kingdom
Nilesh J. Samani
Department of Cardiovascular Sciences, University of Leicester, United Kingdom

Corresponding Author

Email: Robert.Clarke@ctsu.ox.ac.uk

Competing Interests

The Clinical Trial Service Unit has a policy of not accepting honoraria or other payments from the pharmaceutical industry, except for reimbursement of costs to participate in scientific meetings (RCl, DAB, SP, JCH, RCo, RP). PV and MDK are employees of Unilever R&D Vlaardingen, The Netherlands. Unilever makes no claims regarding B-vitamins, homocysteine, and CVD on their food products, and PV and MDK have worked on the paper due to their expertise and data from previous academic life. PV and MDK therefore do not consider this to be a competing interest but declare it for reasons of transparency. HH is an employee of deCode, a biotechnology company that produces genetic testing services. JD and RCo are on the Editorial Board of PLoS Medicine. All other authors have declared that no competing interests exist.

Author Contributions

Conceived and designed the experiments: RCl SP RP. Performed the experiments: RCl DAB SP RP. Analyzed the data: RCl DAB SP RP. Contributed reagents/materials/analysis tools: RCl DAB SP PV MDK ML PX BGN HH JCH DS TT SSA JCC MEK WHO YY CE BP AFRS MMR BT SY JCE TLA JK JD HW NJS RCo RP. Wrote the first draft of the manuscript: RCl SP DAB RP. Contributed to the writing of the manuscript: RCl DAB SP RP. ICMJE criteria for authorship read and met: RCl DAB SP PV MDK ML PX BGN HH JCH DS TT SSA JCC MEK WHO YY CE BP AFRS MMR BT SY JCE TLA JK JD HW NJS RCo RP. Agree with manuscript results and conclusions: RCl DAB SP PV MDK ML PX BGN HH JCH DS TT SSA JCC MEK WHO YY CE BP AFRS MMR BT SY JCE TLA JK JD HW NJS RCo RP.