Abstract
BACKGROUND: Observational studies have indicated that gastroesophageal reflux disease (GERD) is connected to myocardial infarction (MI). Nonetheless, the question of causality in these relationships remains unresolved, given the potential influence of confounding variables. The aim is to study the causal link of GERD with MI and determine whether MI factors have any mediation effects in the causative chain. METHODS: GERD (129,080 cases and 473,524 controls) and MI (831,000 individuals) were obtained from the latest genome-wide association study summary-level data. Two-sample Mendelian randomization (MR) analyses were performed to assess the associations of genetically predicted GERD with MI risk. After adjusting for several confounders, multivariable MR was employed to determine the independent impacts of GERD on MI risk. Two-step MR analyses were carried out to investigate the mediating impacts of these modifiable factors in the relationships between GERD and MI. RESULTS: The current univariable MR analysis indicated that GERD was connected to MI (odds ratio [OR] = 1.61; 95% confidence interval [CI]: 1.48-1.76; p = 1.01 × 10(-26)), whereas this correlation remained after controlling for body mass index, cigarettes per day, and alcohol consumption. Two-step MR found that several MI-associated risk factors mediated the associations between GERD and MI, with hypertension (mediation proportion: 14.4%) and type-2 diabetes mellitus (12.0%) exhibiting higher mediation proportions among the mediating networks. CONCLUSION: This study identifies modifiable cardiovascular risk factors that may mediate the GERD-MI association, with hypertension (14.4%) and T2DM (12.0%) identified as the predominant modifiable mediators. These findings highlight the clinical importance of integrated cardiometabolic monitoring in GERD patients, suggesting that targeted management of blood pressure and glycemic control may mitigate MI risk in GERD populations.