Causal associations of gastroesophageal reflux disease with sepsis and sepsis mortality within 28 days

Previous studies have demonstrated a potential correlation between gastroesophageal reflux disease (GERD) and sepsis. However, the causal association between GERD and sepsis remains unclear. We performed a bidirectional 2-sample Mendelian randomization (MR) analysis to investigate the causal associations of GERD with sepsis and sepsis mortality within 28 days. The inverse variance weighted method was used as a major method for the MR study, supplemented with multiple approaches, including MR-Egger, weighted median, and weighted mode. Then, the MR-Egger intercept test, Mendelian randomized polymorphism residual and outlier (MR-PRESSO) test, Cochran’s Q test, and leave-one-out test were conducted to assess the reliability of the MR results. Forward MR analysis indicated that GERD significantly increased the risk of sepsis (odd ratio [OR] = 1.36; 95% confidence interval [CI]: 1.21–1.52, P = 1.44E−07) and 28-day sepsis mortality (OR = 1.44; 95% CI: 1.08–1.92, P = .014). Reverse MR analysis indicated that sepsis didn’t causally affect GERD, while 28-day sepsis mortality showed a suggestive positive association with GERD (OR = 1.03; 95% CI: 1.01–1.06, P = .015), with a modest but statistically significant effect size. In addition, the MR analyses were found to be robust based on sensitivity tests, indicating no presence of heterogeneity or horizontal pleiotropy. Our study indicated that genetically predicted GERD increases the risk of sepsis and 28-day sepsis mortality, while genetically predicted 28-day sepsis mortality may also increase the risk of GERD, presenting a novel approach to the preventive strategy for sepsis and therapeutic perspectives in patients with GERD. However, given the lenient SNP threshold and small effect size in reverse MR analysis, as well as the exclusive European study cohort, additional studies are required to validate our findings.