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Sci Rep. 2017 Sep 12;7(1):11303. doi: 10.1038/s41598-017-09396-7.

Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium.

Author information

1
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
2
Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
3
National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.
4
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
5
DZHK (German Centre for Cardiovascular Research), partner site: Munich Heart Alliance, Munich, Germany.
6
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
7
Department of Medicine I, University Hospital Munich, Ludwig-Maximilians-University, Munich, Germany.
8
Icelandic Heart Association, 201, Kopavogur, Iceland.
9
Faculty of Medicine, University of Iceland, 101, Reykjavik, Iceland.
10
Population Health Research Institute, Hamilton, Canada.
11
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada.
12
Department of Medicine, Vanderbilt University, Nashville, TN, USA.
13
Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen, Denmark.
14
Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
15
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
16
Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
17
Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany.
18
Department of Cardiology, Lund University and Skåne University Hospital, Lund, Sweden.
19
Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
20
Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA.
21
Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
22
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
23
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
24
Department of Epidemiology, Erasmus Medical Center, University Medical Center, Rotterdam, The Netherlands.
25
Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
26
DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
27
Center for Human Genetic Research, Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
28
Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
29
Divisions of Preventive Medicine and Genetics, Brigham and Women's Hospital, Boston, MA, USA.
30
Research unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
31
Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
32
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, Maryland, 20892, USA.
33
Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston Salem, NC, USA.
34
Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
35
Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA.
36
Departments of Medicine and Biomedical Informatics, Vanderbilt University, Nashville, TN, USA.
37
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
38
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
39
Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
40
Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA.
41
Kaiser Permanente Washington Health Research Institute, Kaiser Foundation Health Plan of Washington, Seattle, WA, USA.
42
Cardiovascular Health Research Unit, Division of Cardiology, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA, USA.
43
Division of Genomic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA.
44
Department of Clinical Physiology, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
45
Department of Cardiology, Heart Center, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
46
Department of Clinical Sciences, Lund University, Malmö, Sweden.
47
Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
48
Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Sandvika, Norway.
49
Institute of Health and Wellbeing, University of Glasgow, Scotland, United Kingdom.
50
Robertson Center for Biostatistics, University of Glasgow, Scotland, United Kingdom.
51
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
52
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
53
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
54
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
55
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
56
Population Health Research Institute, McMaster University, Hamilton, Canada.
57
University Hospital Basel, Basel, Switzerland.
58
Cardiovascular Research Institute Basel, Basel, Switzerland.
59
Departments of Medicine, Clinical Pharmacology, and Biomedical Informatics, Vanderbilt University, Nashville, TN, USA.
60
Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, USA.
61
Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA, USA.
62
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, Graz, Austria.
63
Division of Genomic Outcomes, Departments of Pediatrics and Medicine, Harbor-UCLA Medical Center, Torrance, California, USA.
64
Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands.
65
Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
66
Department of Epidemiology and Internal Medicine, Erasmus University Medical Center Rotterdam, Utrecht, The Netherlands.
67
Inspectorate of Health Care, Utrecht, The Netherlands.
68
Divisions of Preventive Medicine and Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.
69
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. slubitz@mgh.harvard.edu.
70
Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. slubitz@mgh.harvard.edu.

Abstract

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.

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