Although gastroesophageal reflux disease (GERD) is associated with an increased risk for idiopathic pulmonary fibrosis (IPF), no evidence has demonstrated that the reverse is true—that is, that IPF increases an individual’s risk for GERD—according to findings from a bidirectional, two-sample Mendelian randomization (MR) analysis published in the European Respiratory Journal.

Several environmental exposures have been hypothesized as being causally linked to the development of IPF, including diabetes, smoking, and GERD. In the current analysis, the researchers used an MR approach in which genetic variants that are known to impact GERD are used as instrumental variables in an effort to tackle issues of reverse and confounding causation, thus evaluating the ways in which GERD and IPF may be related in a causative fashion.

The two-sample MR used summary statistics for gene-exposure and gene-outcome relationships, which were derived from separate studies. Regarding the MR of the effect of GERD on IPF risk, instruments were chosen from the largest genome-wide association study (GWAS) meta-analysis conducted on GERD.

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The causal effect of GERD on risk for IPF and the causal effect of IPF on risk for GERD were initially calculated by obtaining single nucleotide polymorphism (SNP)-specific MR estimates via use of the Wald estimator (ie, gene outcome divided by gene exposure). The values derived were then pooled with the use of inverse-variance weighted, fixed-effect meta-analysis.

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The inverse-variance weighted, fixed-effect technique was selected for the primary MR analyses as it is the most powerful tool, despite the fact that is assumes the absence of pleiotropy—that is, “variants chosen as instruments for the exposure cannot affect the outcome through any other independent pathways,” according to the authors. Because pleiotropy can bias MR results, its potential presence was explored via evaluation of the heterogeneity of the MR estimates across SNPs.

Based on the GWAS on GERD, 59 independent genome-wide significant SNPs were identified from a sample of 78,707 cases of GERD and 288,734 controls. The sample comprised individuals who were almost entirely of White European ancestry. According to the MR analysis, GERD is associated with a significantly increased risk for IPF (odds ratio [OR], 1.61; 95% CI, 1.04-2.49; P =.032).

The GWAS meta-analysis was based on 4125 individuals with IPF and 20,464 controls. Again, the participants were of White European ancestry. Among 19 SNPs, 15 were absent from the GERD GWAS meta-analysis database. Based on MR analysis, no evidence was seen of a significant causal effect of IPF on risk for GERD (OR, 0.999; 95% CI, 0.997-1.001; P =.245).

“GERD should be considered in future studies of IPF risk, and interest in it as a potential therapeutic target should be renewed,” the researchers noted. “The mechanisms underlying the effect of GERD on IPF should also be investigated,” they concluded.


Reynolds CJ, Del Greco M F, Allen RJ, et al. The causal relationship between gastro-esophageal reflux disease and idiopathic pulmonary fibrosis: a bidirectional two-sample Mendelian randomization study. Eur Respir J. Published online April 20, 2023. doi:10.1183/13993003.01585-2022