Type 2 Diabetes and Atrial Fibrillation: Evaluating Causal and Pleiotropic Pathways Using Mendelian Randomization

Abstract

Background Observational associations between type 2 diabetes (T2D) and atrial fibrillation (AF) have been established, but causality remains undetermined. We performed Mendelian randomization (MR) to study causal effects of genetically predicted T2D on AF risk, independent of cardiometabolic risk factors. Methods and Results Instrumental variables included 182 uncorrelated single nucleotide polymorphisms associated with T2D at genome-wide significance (P <5×10^-8). Genetic association estimates for cardiometabolic exposures were obtained from genome-wide association studies including 188 577 individuals for low-density lipoprotein-C, 694 649 individuals for body mass index, and 757 601 for systolic blood pressure. Two-sample, inverse-variance weighted MR formed the primary analyses. The MR-TRYX approach was used to dissect potential pleiotropic pathways, with multivariable MR performed to investigate cardiometabolic mediation. Genetically predicted T2D associated with increased AF liability in univariable MR (odds ratio [OR], 1.08 [95% CI, 1.02-1.13], P=0.003). Sensitivity analyses indicated potential pleiotropy, with radial MR identifying 4 outlier single nucleotide polymorphisms that were likely contributors. Phenomic scanning on MR-base and subsequent least absolute shrinkage and selection operator regression allowed prioritization of 7 candidate traits. The outlier-adjusted effect estimate remained consistent with the original inverse-variance weighted estimate (OR, 1.07 [95% CI, 1.02-1.12], P=0.008). On multivariable MR, T2D remained associated with increased AF liability after adjustment for low-density lipoprotein-C and body mass index. Following adjustment for systolic blood pressure, the relationship between T2D and AF became nonsignificant (OR, 1.04 [95% CI, 0.95-1.13], P=0.40). Conclusions These data provide novel genetic evidence that while T2D likely causally associates with AF, mediation via systolic blood pressure exists. Endeavoring to lower systolic blood pressure alongside achieving normoglycemia may provide particular benefit on AF risk in patients with T2D.

Keywords: Mendelian randomization; atrial fibrillation; diabetes, type 2; genes.

Figure 1. Study design framework.

AF indicates atrial fibrillation; GWAS, genome‐wide association study; LASSO, least absolute shrinkage and selection operator; MR, Mendelian randomization; MVMR, multivariable Mendelian randomization; SNP, single‐nucleotide polymorphism; and T2DM, type 2 diabetes mellitus.

Figure 2. Forest plots showing Mendelian randomization (MR) summary estimates for the association between type 2 diabetes and AF.

A, Univariable MR and sensitivity analyses for detection of pleiotropy. B, Multivariable MR incorporating single‐nucleotide polymorphisms responsible for pleiotropy. AF indicates atrial fibrillation; BMI, body mass index; LDL, low‐density lipoprotein; MR, Mendelian randomization; PRESSO, Pleiotropy REsidual Sum and Outlier; and SBP, systolic blood pressure.

Figure 3. Effect estimates for type 2 diabetes on AF after adjusting the SNP effects based on the candidate traits, represented as Radial plots of MR associations.

The x axis represents the weight (w) contributed by each SNP to the overall effect estimate, and the y axis represents the product of the weight (w) and the MR effect estimate (beta). The lines indicate the causal effect estimates using different outlier adjustment models. Four identified outlier SNPs are highlighted with blue labels, and the arrows depict the changes in the SNPʼs contribution to the overall causal effect estimate after adjustment for the effect of 1 or more pleiotropic traits, listed in the green text box for each SNP, on the outcome. AF indicates atrial fibrillation; MR, Mendelian randomization; SNP, single‐nucleotide polymorphism; and w, weight.