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 (4125 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 0.999 (95%CI: 0.997–1.000; p=0.245).
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.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Louise Wain reports grants from Orion Pharma, GSK, Genentech, AstraZeneca; consulting fees from Galapagos, Boehringer Ingelheim; travel support from Genentech; advisory board participation with Galapagos; outside the submitted work. Louise Wain is an Associate Editor for the European Respiratory Journal.
Conflict of interest: Toby Maher reports consulting fees from Boehringer Ingelheim, Roche/Genentech, Astra Zeneca, Bayer, Blade Therapeutics, Bristol-Myers Squibb, Galapagos, Galecto, GlaxoSmithKline, IQVIA, Pliant, Respivant, Theravance, Veracyte; lecture honoraria form Boehringer Ingelheim, Roche/Genentech; outside the submitted work.
Conflict of interest: Philip Molyneaux reports grants from AstraZeneca; consulting fees from Hoffman-La Roche, Boehringer Ingelheim, Trevi, Redex, AstraZeneca; lecture honoraria from Boehringer Ingelheim, Hoffman-La Roche; outside the submitted work.
Conflict of interest: Gisli Jenkins reports grants from Astra Zeneca, Biogen, Galecto, GlaxoSmithKline, RedX, Pliant, Genetech; consulting fees from Bristol Myers Squibb, Daewoong, Veracyte, Resolution Therapeutics, RedX, Pliant, Chiesi; advisory board participation with Boehringer Ingelheim, Galapagos, Vicore, Roche; leadership role with NuMedii; leadership role and trustee for Action for Pulmonary Fibrosis; outside the submitted work.
Conflict of interest: All other authors have nothing to disclose.
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