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J Am Coll Cardiol. 2014 Apr 1;63(12):1200-10. doi: 10.1016/j.jacc.2013.12.015. Epub 2014 Jan 30.

Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.

Author information

  • 1Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: slubitz@partners.org.
  • 2Boston University and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; Department of Biostatistics, School of Public Health, Boston University, Boston, Massachusetts.
  • 3Boston University and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
  • 4McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • 5Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands; Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
  • 6Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington.
  • 7Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Netherlands Consortium on Healthy Aging (NCHA), Leiden, the Netherlands.
  • 8Harvard Medical School, Boston, Massachusetts; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
  • 9Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
  • 10Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany.
  • 11Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Greifswald Greifswald, Germany.
  • 12Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • 13Icelandic Heart Association, Kopavogur Iceland and University of Iceland, Reykjavik, Iceland.
  • 14Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany; Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians University, Munich, Germany.
  • 15Department of Society, Human Development & Health, Harvard School of Public Health, Boston, Massachusetts.
  • 16Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland.
  • 17Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota.
  • 18Harvard Medical School, Boston, Massachusetts; Division of Cardiology, Brigham and Women's Hospital, Boston, Massachusetts.
  • 19Robertson Center for Biostatistics, University of Glasgow, Glasgow, Scotland.
  • 20Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
  • 21Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany; Deutsches Forschungszentrum für Herz-Kreislauferkrankungen (DZHK), Partner site Munich Heart Alliance, Munich, Germany.
  • 22Leeds General Infirmary, Leeds, England.
  • 23Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts.
  • 24Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • 25Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland.
  • 26Boston University and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
  • 27Department of Biostatistics, University of Washington, Seattle, Washington.
  • 28Departments of Medicine and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts.
  • 29Deutsches Forschungszentrum für Herz-Kreislauferkrankungen (DZHK), Partner site Munich Heart Alliance, Munich, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
  • 30Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington; Department of Health Services, University of Washington, Seattle, Washington; Department of Epidemiology, University of Washington, Seattle, Washington; Group Health Research Institute, Group Health Cooperative, Seattle, Washington.
  • 31Division of Preventive Medicine, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
  • 32Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.
  • 33Department of Angiology, Swiss Cardiovascular Centre, Bern University Hospital, Bern, Switzerland.
  • 34Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
  • 35Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington; Division of Cardiology, University of Washington, Seattle, Washington.
  • 36Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California.
  • 37Department of Cardiology, Medical University of Graz, Graz, Austria.
  • 38Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • 39Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Netherlands Consortium on Healthy Aging (NCHA), Leiden, the Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
  • 40Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
  • 41DZHK (German Centre for Cardiovascular Research), Partner site Greifswald Greifswald, Germany; Interfaculty Institute for Genetics and Functional Genomics, Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
  • 42DZHK (German Centre for Cardiovascular Research), Partner site Greifswald Greifswald, Germany; Institute for Community Medicine, Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
  • 43Boston University and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
  • 44Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
  • 45Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany; Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria; Synlab Academy, Synlab Services GmbH, Mannheim, Germany.
  • 46Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio.
  • 47Harvard Medical School, Boston, Massachusetts; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts; Division of Cardiology, Brigham and Women's Hospital, Boston, Massachusetts.
  • 48Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Netherlands Consortium on Healthy Aging (NCHA), Leiden, the Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands; Inspectorate for Health Care, the Hague, the Netherlands.
  • 49Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
  • 50Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington; Department of Epidemiology, University of Washington, Seattle, Washington; Group Health Research Institute, Group Health Cooperative, Seattle, Washington.
  • 51Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands, and Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands.
  • 52Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota.
  • 53Boston University and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; Department of Epidemiology, School of Public Health, Boston University, Boston, Massachusetts; Preventive Medicine Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
  • 54Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts.

Abstract

OBJECTIVES:

This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.

BACKGROUND:

AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.

METHODS:

We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).

RESULTS:

We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.

CONCLUSIONS:

The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.

Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

KEYWORDS:

atrial fibrillation; atrial flutter; genetic; prognosis; risk

PMID:
24486271
[PubMed - indexed for MEDLINE]
PMCID:
PMC4009240
Free PMC Article
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