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

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 ev...

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Published in:Circulation (New York, N.Y.) N.Y.), 2017-02, Vol.135 (8), p.741-754
Main Authors: Chatterjee, Neal A, Giulianini, Franco, Geelhoed, Bastiaan, Lunetta, Kathryn L, Misialek, Jeffrey R, Niemeijer, Maartje N, Rienstra, Michiel, Rose, Lynda M, Smith, Albert V, Arking, Dan E, Ellinor, Patrick T, Heeringa, Jan, Lin, Honghuang, Lubitz, Steven A, Soliman, Elsayed Z, Verweij, Niek, Alonso, Alvaro, Benjamin, Emelia J, Gudnason, Vilmundur, Stricker, Bruno H C, Van Der Harst, Pim, Chasman, Daniel I, Albert, Christine M
Format: Article
Language:English
Subjects:
Aged
Alleles
Alpha-Ketoglutarate-Dependent Dioxygenase FTO - genetics
Atrial Fibrillation - epidemiology
Atrial Fibrillation - etiology
Body Mass Index
Cohort Studies
Female
Genotype
Humans
Incidence
Male
Middle Aged
Obesity - genetics
Obesity - pathology
Polymorphism, Single Nucleotide
Proportional Hazards Models
Prospective Studies
Random Allocation
Risk Factors
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Summary: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 usedFTO 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 (FTO0.43 [95% confidence interval, 0.32–0.54] kg/m per A-allele, P
ISSN:0009-7322
1524-4539
1524-4539
DOI:10.1161/CIRCULATIONAHA.116.024921