Genetic Obesity and the Risk of Atrial Fibrillation Causal Estimates from Mendelian Randomization

• Type of Material: Article
• Authors: Neal A. Chatterjee, Harvard Medical School; Franco Giulianini, Harvard Medical School; Bastiaan Geelhoed, University of Groningen; Kathryn Lunetta, Framingham Heart Study; Jeffrey R. Misialek, University of Minnesota; Maartje N. Niemeijer, Erasmus Medical Center-University Medical Center; Michiel Rienstra, University of Groningen; Lynda M. Rose, Harvard Medical School; Albert V. Smith, Iceland Heart Assoc; Dan E. Arking, Johns Hopkins University; Patrick T. Ellinor, Massachusetts General Hospital; Jan Heeringa, Erasmus Medical Center-University Medical Center; Honghuang Lin, Framingham Heart Dis Epidemiol Study; Steven A. Lubitz, Massachusetts General Hospital; Elsayed Z. Soliman, Epidemiological Cardiology Research Center (EPICARE); Niek Verweij, University of Groningen; Alvaro Alonso, Emory University; Emelia J. Benjamin, Framingham Heart Study; Vilmundur Gudnason, University of Iceland; Bruno H. C. Stricker, Erasmus Medical Center-University Medical Center; Pim Van Der Harst, University of Groningen; Daniel I. Chasman, Harvard Medical School; Christine M. Albert, Harvard Medical School
• Language: English
• Date: 2017-02-21
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 American Heart Association, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/CIRCULATIONAHA.116.024921
• Title of Journal or Parent Work: Circulation
• ISSN: 0009-7322
• Volume: 135
• Issue: 8
• Start Page: 741
• End Page: +
• Grant/Funding Information: Dr Chatterjee is supported by NHLBI T-32 HL-007575 (Bethesda, Maryland).; WGHS: The Women’s Genome Health Study and AF end point confirmation was supported by HL043851, HL080467, HL093613, and HL099355 (completed) from the National Heart, Lung, and Blood Institute, CA047988 (completed) and UM1CA182913 from the National Cancer Institute, and the Watkin’s Foundation, with collaborative scientific support and funding for genotyping provided by Amgen.; D. Lubitz is supported by NIH grant K23HL114724 and a Doris Duke Charitable Foundation Clinical Scientist Development Award 2014105.; FHS: The Framingham Heart Study is supported by National Heart, Lung, and Blood Institute contracts HHSN268201500001I; N01-HC 25195; 2R01HL092577; 1R01HL128914; completed 1R01 HL102214; 1RC1HL101056; K24HL105780.; Dr Alonso is supported by American Heart Association grant 16EIA26410001.; Infrastructure was partly supported by grant number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research.; Dr Ellinor is supported by an Established Investigator Award from the American Heart Association (13EIA14220013) and by the Foundation Leducq (14CVD01).; Dr Rienstra is supported by a grant from the Netherlands Organization for Scientific Research (Veni grant 016·136·055).; AGES: The Age, Gene/Environment Susceptibility-Reykjavik Study was supported by National Institutes of Health (contracts N01-AG-12100 and HHSN271201200022C), the National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament).; ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C.; PREVEND: The Prevention of Renal and Vascular End-Stage Disease study is supported by the Dutch Kidney Foundation (grant E0.13) and the Netherlands Heart Foundation (NHS2010B280). Rotterdam Study: The Rotterdam Study is supported by the Erasmus MC University Medical Center, the Netherlands Organization for Scientific Research (NWO), the Netherlands Organization for Health Research and Development, the Netherlands Genomics Initiative, and the municipality of Rotterdam.
• Keywords: SECULAR TRENDS; Science & Technology; HEART-FAILURE; Cardiovascular System & Cardiology; WEIGHT CHANGE; epidemiology; prevention & control; atrial fibrillation; WOMENS HEALTH; obesity; BODY-MASS INDEX; Life Sciences & Biomedicine; ATHEROSCLEROSIS RISK; MORTALITY; Cardiac & Cardiovascular Systems; CARDIOVASCULAR HEALTH; EARLY-CHILDHOOD; genetics; Peripheral Vascular Disease; GLOBAL BURDEN
• Research Categories: Health Sciences, Epidemiology; Health Sciences, Public Health

Abstract

Background: Observational studies have identified an association between body mass index (BMI) and incident atrial fibrillation (AF). Inferring causality from observational studies, however, is subject to residual confounding, reverse causation, and bias. The primary objective of this study was to evaluate the causal association between BMI and AF by using genetic predictors of BMI. Methods: We identified 51 646 individuals of European ancestry without AF at baseline from 7 prospective population-based cohorts initiated between 1987 and 2002 in the United States, Iceland, and the Netherlands with incident AF ascertained between 1987 and 2012. Cohort-specific mean follow-up ranged from 7.4 to 19.2 years, over which period there was a total of 4178 cases of incident AF. We performed a Mendelian randomization with instrumental variable analysis to estimate a cohort-specific causal hazard ratio for the association between BMI and AF. Two genetic instruments for BMI were used: FTO genotype (rs1558902) and a BMI gene score comprising 39 single-nucleotide polymorphisms identified by genome-wide association studies to be associated with BMI. Cohort-specific estimates were combined by random-effects, inverse variance-weighted meta-analysis. Results: In age- and sex-adjusted meta-analysis, both genetic instruments were significantly associated with BMI (FTO: 0.43 [95% confidence interval, 0.32-0.54] kg/m 2 per A-allele, P < 0.001; BMI gene score: 1.05 [95% confidence interval, 0.90-1.20] kg/m 2 per 1-U increase, P < 0.001) and incident AF (FTO, hazard ratio, 1.07 [1.02-1.11] per A-allele, P=0.004; BMI gene score, hazard ratio, 1.11 [1.05-1.18] per 1-U increase, P < 0.001). Age- and sex-adjusted instrumental variable estimates for the causal association between BMI and incident AF were hazard ratio, 1.15 (1.04-1.26) per kg/m 2 , P=0.005 (FTO) and 1.11 (1.05-1.17) per kg/m 2 , P < 0.001 (BMI gene score). Both of these estimates were consistent with the meta-analyzed estimate between observed BMI and AF (age- and sex-adjusted hazard ratio 1.05 [1.04-1.06] per kg/m 2 , P < 0.001). Multivariable adjustment did not significantly change findings. Conclusions: Our data are consistent with a causal relationship between BMI and incident AF. These data support the possibility that public health initiatives targeting primordial prevention of obesity may reduce the incidence of AF.