Rheumatoid arthritis and gastroesophageal reflux disease: a bidirectional and multivariable two-sample Mendelian randomization study

Aims/hypothesis: The association between gastroesophageal reflux disease (GERD) and rheumatoid arthritis (RA) has been reported by many observational studies in the Asian population. This study aimed to examine the bidirectional causal effects between GERD and RA by two-sample Mendelian randomization (MR) analyses using genetic evidence. Methods: Two-sample Mendelian randomization analyses were performed to determine the causal effect of GERD (129,080 cases vs. 602,604 control participants) on RA (6,236 cases vs. 147,221 control participants) and RA on GERD, respectively. The inverse-variance weighted (IVW) method was used as the primary analysis. Weighted median and MR-Egger regression were taken as supplementary analyses. Cochran's Q test evaluated the heterogeneity. Horizontal pleiotropy was detected by estimating the intercept term of MR-Egger regression. Furthermore, multivariable MR analyses were performed to exclude the influence of confounding factors, including the years of schooling, BMI, and time spent watching television, between GERD and RA.Result: Both univariate MR (UVMR) and multivariable MR (MVMR) provided valid evidence that RA was causally and positively influenced by GERD (UVMR: OR = 1.49, 95% CI = 1.25-1.76,p = 6.18*10-6; MVMR: OR = 1.69, 95% CI = 1.24-2.31, p = 8.62*10-4), whereas GERD was not influenced by RA (UVMR: OR = 1.03, 95% CI = 1.00-1.06, p = 0.042; MVMR: OR = 1.04, 95% CI = 1.00-1.07, p = 0.0271).Conclusion: Our comprehensive bidirectional MR analysis found that for the European population, GERD can induce the occurrence of RA (OR = 1.69, p < 0.00125), whereas RA only has no significant influence on GERD. In particular, patients with GERD are suffering a 69% increased risk of RA occurrence, which means GERD is a substantial risk factor for RA.