The causal relationship between gastro-esophageal reflux disease and idiopathic pulmonary fibrosis: A bidirectional two-sample Mendelian randomization study

Abstract Background Gastro-esophageal reflux disease (GERD) is associated with idiopathic pulmonary fibrosis (IPF) in observational studies. It is not known if this association arises because GERD causes IPF, or IPF causes GERD, or because of confounding by factors, such as smoking, associated with both GERD and IPF. We used bidirectional Mendelian randomisation (MR), where genetic variants are used as instrumental variables to address issues of confounding and reverse causation, to examine how, if at all, GERD and IPF are causally related. Methods and results A bidirectional two-sample MR was performed to estimate the causal effect of GERD on IPF risk, and of IPF on GERD risk, using genetic data from the largest GERD (78,707 cases and 288,734 controls) and IPF (4,125 cases and 20,464 controls) genome-wide association meta-analyses currently available. GERD increased the risk of IPF, with an odds ratio (OR) of 1.6 (95% Confidence Interval, CI: 1.04-2.49; p=0.032). There was no evidence of a causal effect of IPF on the risk of GERD, with an OR of 0.99 (95%CI: 0.97-1.02; p=0.615). Conclusion We found that GERD increases the risk of IPF, but found no evidence that IPF increases the risk of GERD. GERD should be considered in future studies of IPF risk, and interest in it as a potential therapeutic target should be renewed. The mechanisms underlying the effect of GERD on IPF should also be investigated.