Body composition and atrial fibrillation: a Mendelian randomization study

Abstract

Aims: Increases in fat-free mass and fat mass have been associated with higher risk of atrial fibrillation (AF) in observational studies. It is not known whether these associations reflect independent causal processes. Our aim was to evaluate independent causal roles of fat-free mass and fat mass on AF.

Methods and results: We conducted a large observational study to estimate the associations between fat-free mass and fat mass on incident AF in the UK Biobank (N = 487 404, N events = 10 365). Genome-wide association analysis was performed to obtain genetic instruments for Mendelian randomization (MR). We evaluated the causal effects of fat-free mass and fat mass on AF with two-sample method by using genetic associations from AFGen consortium as outcome. Finally, we evaluated independent causal effects of fat-free mass and fat mass with multivariate MR. Both fat-free mass and fat mass had observational associations with incident AF [hazard ratio (HR) = 1.77, 95% confidence interval (CI) 1.72-1.83; HR = 1.40, 95% CI 1.37-1.43 per standard deviation increase in fat-free and fat mass, respectively]. The causal effects using the inverse-variance weighted method were 1.55 (95% CI 1.38-1.75) for fat-free mass and 1.30 (95% CI 1.17-1.45) for fat mass. Weighted median, Egger regression, and penalized methods showed similar estimates. The multivariate MR analysis suggested that the causal effects of fat-free and fat mass were independent of each other (causal risk ratios: 1.37, 95% CI 1.06-1.75; 1.28, 95% CI 1.03-1.58).

Conclusion: Genetically programmed increases in fat-free mass and fat mass independently cause an increased risk of AF.

Keywords: Atrial fibrillation; Bioimpedance; Causal effect; Fat mass; Fat-free mass; Genetics.

Figure 1

Flowchart of the data sources and statistical analyses.

Figure 2

Effect sizes for genetic instruments for body composition traits used in multivariate Mendelian randomization analysis.

Figure 3

Relations of body composition and atrial fibrillation events. Lines are based on a regression spline of Cox proportional hazards.

Take home figure

Observational associations and causal effects of body composition measures on atrial fibrillation. All effects are in SD-units. Observational, Model 1: Cox regression model adjusted for age, sex, and region. Observational, Model 2: Cox regression model adjusted for age, sex, region, physical activity, smoking, alcohol consumption, blood pressure, diabetes, and lipid medication. Multivariate causal: the causal effects of fat-free and fat mass adjusted for each other. CI, confidence interval; IVW, inverse-variance weighted.