A Mendelian randomization study to assess the genetic liability of gastroesophageal reflux disease for cardiovascular diseases and risk factors

Abstract Observational studies have reported that gastroesophageal reflux disease (GERD) is a risk factor for cardiovascular diseases (CVD); however, the causal inferences between them remain unknown. We conducted a Mendelian randomization (MR) study to estimate the causal associations between GERD and 10 CVD outcomes, as well as 14 cardiovascular risk factors. We used summary statistics from genome-wide association studies for GERD and the FinnGen consortium for CVD. We further investigated whether GERD correlated with cardiovascular risk factors and performed multivariable MR and mediation analyses to estimate the mediating effects of these risk factors on GERD–CVD progression. Sensitivity analyses and replication analyses were also performed. Our results indicated that GERD was positively associated with seven CVD outcomes with odds ratios of 1.26 [95% confidence interval (CI), 1.15, 1.37] for coronary artery disease, 1.41 (95% CI, 1.28, 1.57) for myocardial infarction, 1.34 (95% CI, 1.19, 1.51) for atrial fibrillation, 1.34 (95% CI, 1.21, 1.50) for heart failure, 1.30 (95% CI, 1.18, 1.43) for any stroke, 1.19 (95% CI, 1.06, 1.34) for ischemic stroke and 1.29 (95% CI, 1.16, 1.44) for venous thromboembolism. Furthermore, GERD was associated with nine cardiovascular risk factors and major depressive disorder demonstrated significant mediation effects on the causal pathway linking GERD and any stroke. This study demonstrates that GERD is associated with seven CVD outcomes and nine cardiovascular risk factors. Importantly, GERD treatment may help prevent common CVD events.