Causal associations between atrial fibrillation and breast cancer: A bidirectional Mendelian randomization analysis

Abstract

Background: Previous observational studies indicated that atrial fibrillation may increase the risk of breast cancer. Following a breast cancer diagnosis, the chance of developing atrial fibrillation may increase as well. However, it is uncertain whether the link is causal or just due to confounding factors.

Objective: Using bidirectional Mendelian randomization (MR) analysis, we sought to assess the bidirectional causal relationship between atrial fibrillation and breast cancer from a genetic level.

Methods: Large genome-wide association studies yielded summary-level data for atrial fibrillation and breast cancer. The preliminary estimate was inverse variance weighted (IVW) under a random model. MR-Egger, weighted median, simple mode, weighted mode, and multivariable MR (adjusting body mass index, smoking, and alcohol drinking) were performed as sensitivity analyses.

Results: Genetically predicted atrial fibrillation presented no statistically significant association with overall breast cancer (odds ratio [OR] = 1.00; 95% confidence interval [CI]: 0.97-1.04; p = 0.79), estrogen receptor (ER) + (OR = 1.00; 95% CI: 0.96-1.03; p = 0.89) or ER- subtypes (OR = 1.00; 95% CI: 0.97-1.04; p = 0.89). Similarly, genetically predicted overall breast cancer (OR = 1.01; 95% CI: 0.98-1.04; p = 0.37), ER+ (OR = 1.02; 95% CI: 0.99-1.05; p = 0.16) or ER- (OR = 0.98; 95% CI: 0.93-1.02; p = 0.32) subtypes had no causal effect on atrial fibrillation. Sensitivity analyses yielded similar results. Individual single nucleotide polymorphism had little effect on the total estimate. We did not observe any evidence of horizontal pleiotropy.

Conclusions: Our bidirectional MR studies revealed that there may be no causal links between atrial fibrillation and breast cancer.

Keywords: Mendelian randomization; atrial fibrillation; breast cancer; causal association.

FIGURE 1

Mendelian randomization model.

FIGURE 2

Associations between atrial fibrillation and breast cancer. CI, confidence interval; ER, estrogen receptor; OR, odds ratio; SNP, single nucleotide polymorphism.

FIGURE 3

Funnel plot of the associations between atrial fibrillation and breast cancer. A: Atrial fibrillation → Breast cancer; B: Atrial fibrillation → ER+ Breast cancer; C: Atrial fibrillation → ER− Breast cancer; D: Breast cancer → Atrial fibrillation; E: ER+ Breast cancer → Atrial fibrillation; F: ER− Breast cancer → Atrial fibrillation. ER, estrogen receptor.