The causal relationship between gastro-oesophageal reflux disease and idiopathic pulmonary fibrosis: a bidirectional two-sample Mendelian randomisation study

Abstract

BackgroundGastro-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 resultsA 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).ConclusionWe 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.

The Role of Proton Pump Inhibitors in the Realm of Idiopathic Pulmonary Fibrosis and its Associated Comorbidities: A Systematic Review

“…Since a genetic link to GERD is inherent from birth, with MR, we evaluate an individual's lifetime tendency to develop GERD at the risk of IPF. Our results are not affected by any dietary or pharmacological therapy for GERD [ 20 ].…”

“…The negative impact of PPIs in IPF is highlighted in a meta-analysis which reveals that post hoc analysis of two observational studies reveal that antacids don't cause a much decrease in FVC; six-minute walking duration and antireflux surgery revealed similar results [ 8 ]. Two-sample bidirectional Mendelian randomization (MR) reveals GERD is the underlying cause of IPF and not vice versa [ 20 ]. The positive impact of PPIs in observational studies is blurred by lead time bias [ 21 ].…”

The causal relationship between genetically predicted blood metabolites and idiopathic pulmonary fibrosis: A bidirectional two-sample Mendelian randomization study

“…Although confounding bias and reverse causality are common limitations in observational studies, they are less likely to appear in MR analyses since genotype formation precedes disease onset [ 17 ]. Several MR analyses have confirmed the causal relationship between IPF and exposures such as body mass index (BMI) [ 18 ], circulating proteins [ 19 ], comorbidities (including gastroesophageal reflux disease (GERD) [ 20 ], hypothyroidism [ 21 ], venous thromboembolism [ 22 ], chronic obstructive pulmonary disease [ 22 ], and diabetes [ 22 ]).…”

Association between Antacid Exposure and Risk of Interstitial Lung Diseases

“…Gastroesophageal reflux disease (GERD) is an overrepresented comorbidity of interstitial lung disease (ILD)/IPF [ 6 - 10 ], suggesting that micro-aspiration of gastric acids increases the risk of IPF development [ 7 ]. Genetic and population-based studies suggest GERD increases the risk of IPF [ 11 , 12 ]. Chronic micro-aspiration may lead to fibrotic remodeling of the pulmonary parenchyma, resulting in lower pulmonary elasticity and increases negative intrathoracic pressure [ 6 ].…”