Use of Mendelian randomization to evaluate the effect of atrial fibrillation on cardiovascular diseases and cardiac death

Abstract

Aims: Several observational studies indicated that atrial fibrillation might aggravate other cardiovascular diseases apart from ischaemic stroke. However, it remains to be determined whether these associations reveal independent causation. Using Mendelian randomization (MR), we systematically investigated how genetically predicted atrial fibrillation affected other cardiovascular diseases and cardiac death.

Methods and results: Summary-level data for atrial fibrillation and other cardiovascular diseases were obtained from public genome-wide association study data. The random inverse-variance weighted method was treated as the primary analysis. Sensitivity analyses (including weighted median, MR-Egger, and multivariable MR methods) were also performed. Atrial fibrillation was significantly associated with higher risks of heart failure [odds ratio (OR): 1.24; 95% confidence interval (CI): 1.19-1.28; P < 0.001], ischaemic stroke (OR: 1.21; 95% CI: 1.17-1.25; P < 0.001), transient ischaemic attack (OR: 1.10; 95% CI: 1.05-1.15; P < 0.001), peripheral artery diseases (OR: 1.09; 95% CI: 1.03-1.15; P = 0.002), cardiac death (OR: 1.08; 95% CI: 1.02-1.15; P = 0.008), and hypertension (OR: 1.06; 95% CI: 1.01-1.11; P = 0.010), without effects on coronary heart disease or pulmonary embolism. Associations for heart failure and ischaemic stroke remained robust to the sensitivity analyses. MR-Egger method (P > 0.05) and funnel plot yielded no indication of directional pleiotropy. The leave-one-out analysis suggested that the causal associations were not driven by individual single nucleotide polymorphism.

Conclusions: This comprehensive MR analysis verified the causal associations between atrial fibrillation and high risks of heart failure, ischaemic stroke, transient ischaemic attack, peripheral artery diseases, cardiac death, and hypertension. Interventions to reduce cardiovascular diseases beyond ischaemic stroke are warranted in patients with atrial fibrillation.

Keywords: Atrial fibrillation; Coronary heart disease; Heart failure; Hypertension; Ischaemic stroke; Mendelian randomization; Peripheral artery diseases; Pulmonary embolism.

Figure 1

Associations of genetically predicted atrial fibrillation with eight cardiovascular diseases. CI, confidence interval; OR, odds ratio; SNP, single nucleotide polymorphism.

Figure 2

Funnel plot of the association of atrial fibrillation with eight cardiovascular diseases: (A) coronary heart disease, (B) hypertension, (C) heart failure, (D) ischaemic stroke, (E) transient ischaemic attack, (F) pulmonary embolism, (G) peripheral artery disease, and (H) cardiac death. Each black dot indicates a single nucleotide polymorphism. MR, Mendelian randomization.