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

• Type of Material: Article
• Authors: Lu-Chen Weng, Massachusetts General Hospital; Kathryn L. Lunetta, National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study; Martina Müller-Nurasyid, Munich Heart Alliance; Albert Vernon Smith, Icelandic Heart Association; Sébastien Thériault, Population Health Research Institute; Peter E. Weeke, Vanderbilt University; John Barnard, Cleveland Clinic; Joshua C. Bis, University of Washington; Leo-Pekka Lyytikäinen, University of Tampere; Marcus E. Kleber, University of Heidelberg; Andreas Martinsson, Lund University and Skåne University Hospital; Henry J. Lin, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center; Michiel Rienstra, University of Groningen; Stella Trompet, Leiden University Medical Center; Bouwe P. Krijthe, University Medical Center; Marcus Dörr, University Medicine Greifswald; Derek Klarin, Massachusetts General Hospital; Daniel I. Chasman, Brigham and Women's Hospital; Moritz F. Sinner, Munich Heart Alliance; Melanie Waldenberger, Munich Heart Alliance; Lenore J. Launer, National Institutes of Health; Tamara B. Harris, National Institutes of Health; Elsayed Z. Soliman, Wake Forest School of Medicine; Alvaro Alonso, Emory University; Guillaume Paré, Population Health Research Institute; Pedro L. Teixeira, Vanderbilt University; Joshua C. Denny, Vanderbilt University; M. Benjamin Shoemaker, Vanderbilt University Medical Center; David R. Van Wagoner, Cleveland Clinic; Jonathan D. Smith, Cleveland Clinic; Bruce M. Psaty, University of Washington; Nona Sotoodehnia, Kaiser Foundation Health Plan of Washington; Kent D. Taylor, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center; Mika Kähönen, University of Tampere; Kjell Nikus, University of Tampere; Graciela E. Delgado, University of Heidelberg; Olle Melander, Lund University; Gunnar Engström, Lund University; Jie Yao, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center; Xiuqing Guo, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center; Ingrid E. Christophersen, Massachusetts General Hospital; Patrick T. Ellinor, Massachusetts General Hospital; Bastiaan Geelhoed, University Medical Center Groningen; Niek Verweij, University Medical Center Groningen; Peter Macfarlane, University of Glasgow; Ian Ford, University of Glasgow; Jan Heeringa, University Medical Center; Oscar H. Franco, University Medical Center, Rotterdam; André G. Uitterlinden, Erasmus University Medical Center, Rotterdam; Uwe Völker, DZHK (German Centre for Cardiovascular Research), partner site Greifswald; Alexander Teumer, DZHK (German Centre for Cardiovascular Research), partner site Greifswald; Lynda M. Rose, Brigham and Women's Hospital; Stefan Kääb, DZHK (German Centre for Cardiovascular Research), partner site: Munich Heart Alliance; Vilmundur Gudnason, Icelandic Heart Association; Dan E. Arking, Johns Hopkins University School of Medicine; David Conen, McMaster University; Dan M. Roden, Vanderbilt University; Mina K. Chung, Cleveland Clinic; Susan R. Heckbert, Kaiser Foundation Health Plan of Washington; Emelia J. Benjamin, National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study; Terho Lehtimäki, University of Tampere; Winfried März, University of Heidelberg; J. Gustav Smith, Lund University and Skåne University Hospital; Jerome I. Rotter, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center; Pim van der Harst, University Medical Center Groningen; J. Wouter Jukema, Leiden University Medical Center; Bruno H. Stricker, Erasmus University Medical Center Rotterdam; Stephan B. Felix, University Medicine Greifswald; Christine M. Albert, Brigham and Women's Hospital; Steven A. Lubitz, Massachusetts General Hospital
• Language: English
• Date: 2017-09-12
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2017
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-017-09396-7
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 7
• Issue: 1
• Start Page: 11303
• End Page: 11303
• Grant/Funding Information: Dr. Christophersen is supported by a mobility grant from the Research Council of Norway [240149/F20].; Dr. Klarin is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number T32 HL007734.; This work was supported by grants from the NIH K23HL114724 (Lubitz), 1RO1HL092577 and R01HL128914 (Benjamin and Ellinor), K24HL105780 (Ellinor), Doris Duke Charitable Foundation Clinical Scientist Development Award 2014105 (Lubitz), an Established Investigator Award from the American Heart Association 13EIA14220013 (Ellinor), the Fondation Leducq 14CVD01 (Ellinor).
• Research Categories: Health Sciences, Public Health; Health Sciences, Epidemiology

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.