Dataset Information

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

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/m2 per A-allele, P<0.001; BMI gene score: 1.05 [95% confidence interval, 0.90-1.20] kg/m2 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/m2, P=0.005 (FTO) and 1.11 (1.05-1.17) per kg/m2, 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/m2, 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.

SUBMITTER: Chatterjee NA

PROVIDER: S-EPMC5322057 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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

Chatterjee Neal A NA Giulianini Franco F Geelhoed Bastiaan B Lunetta Kathryn L KL Misialek Jeffrey R JR Niemeijer Maartje N MN Rienstra Michiel M Rose Lynda M LM Smith Albert V AV Arking Dan E DE Ellinor Patrick T PT Heeringa Jan J Lin Honghuang H Lubitz Steven A SA Soliman Elsayed Z EZ Verweij Niek N Alonso Alvaro A Benjamin Emelia J EJ Gudnason Vilmundur V Stricker Bruno H C BHC Van Der Harst Pim P Chasman Daniel I DI Albert Christine M CM

Circulation 20161214 8

<h4>Background</h4>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.<h4>Methods</h4>We identified 51 646 individuals of European ancestry without AF at baseline from 7 prospect ...[more]

PMID: 27974350

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Project description:Background: Obesity is a well-established risk factor for atrial fibrillation (AF). Previous epidemiological research on obesity and AF often focused on adult populations and now broadened to earlier in life. Therefore, this study aimed to determine the relationships between obesity at different periods of life and the risk of AF. Methods: A two-sample Mendelian randomization (MR) study design using summarised data from 6 genome-wide association studies (GWASs) was employed in this study. Single nucleotide polymorphisms (SNPs) associated with adult obesity, childhood obesity, childhood body mass index (BMI), waist-to-hip ratio adjusted for BMI (WHRadjBMI), birth weight and AF were independently retrieved from large-scale GWASs. For SNP identification, the genome-wide significance threshold was set at p <5.00×10-8. To obtain causal estimates, MR analysis was conducted using the inverse variance-weighted (IVW) method. The weighted median, MR-Egger methods and MR-robust adjusted profile score (MR-RAPS) were used to evaluate the robustness of MR analysis. Results: A total of 204 SNPs were identified as the genetic instrumental variables (5 SNPs for childhood obesity, 13 SNPs for childhood BMI, 137 SNPs for birth weight, 35 SNPs for adult WHRadjBMI, and 14 SNPs for adult obesity). The results of MR analysis demonstrated that the genetically predicted adult obesity, childhood BMI, and birth weight were associated with AF risk. Notably, a 1 unit standard deviation (1-SD) increase in adult obesity was related to a 13% increased risk of AF [p=6.51×10-7, OR, 1.13 (95% CI, 1.08-1.19)], a 1-SD increase in childhood BMI was related to a 18% increased risk of AF [p=1.77×10-4, OR, 1.18 (95% CI, 1.08-1.29)], and a 1-SD increase in birth weight was related to a 26% increased risk of AF [p=1.27×10-7, OR, 1.26 (95% CI, 1.16-1.37)]. There was no evidence of pleiotropy or heterogeneity between the MR estimates obtained from multiple SNPs. Conclusion: Our study reveals the association of genetic susceptibility to obesity with a higher risk of AF. Moreover, an earlier age at obesity was associated with an increased risk of AF. Therefore, public awareness of the dangers of obesity and active early weight control may prevent the development of AF.

Project description:BackgroundWhether elevated blood pressure (BP) is a modifiable risk factor for atrial fibrillation (AF) is not established. We tested (1) whether the association between BP and risk of AF is causal, (2) whether it varies according to individual's genetic susceptibility for AF, and (3) the extent to which specific BP-lowering drugs are expected to reduce this risk.MethodsFirst, causality of association was assessed through two-sample Mendelian randomization, using data from two independent genome-wide association studies that included a population of one million Europeans in total. Second, the UK Biobank data of 329,237 participants at baseline was used to study the effect of BP on AF according to genetic susceptibility of developing AF. Third, a possible treatment effect with major BP-lowering drug classes on AF risk was predicted through genetic variants in genes encode the therapeutic targets of each drug class. Estimated drug effects were compared with effects on incident coronary heart disease, for which direct trial evidence exists.ResultsThe two-sample Mendelian randomization analysis indicated that, on average, exposure to a higher systolic BP increased the risk of AF by 19% (odds ratio per each 10-mmHg [OR] 1.19 [1.12 to 1.27]). This association was replicated in the UK biobank using individual participant data. However, in a further genetic risk-stratified analysis, there was evidence for a linear gradient in the relative effects of systolic BP on AF; while there was no conclusive evidence of an effect in those with low genetic risk, a strong effect was observed among those with high genetic susceptibility for AF. The comparison of predicted treatment effects using genetic proxies for three main drug classes (angiotensin-converting enzyme inhibitors, beta-blockers, and calcium channel blockers) suggested similar average effects for the prevention of atrial fibrillation and coronary heart disease.ConclusionsThe effect of elevated BP on the risk of AF is likely to be causal, suggesting that BP-lowering treatment may be effective in AF prevention. However, average effects masked clinically important variations, with a more pronounced effect in individuals with high genetic susceptibility risk for AF.

Dataset Information

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

Publications

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

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