Gastroesophageal reflux disease and idiopathic pulmonary fibrosis risk: A mendelian randomization study

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with unknown etiology and treatment options for it were limited. Whether Gastroesophageal reflux disease (GERD) could affect the occurrence of IPF remains unclear. Methods: Using available data from FINNGEN and IEU OpenGWAS, we performed Two-sample mendelian randomization (MR) to explore the causal relationship between GERD and IPF. Results: Using 65 GERD-related SNPs, we found the association between GERD and the risk of IPF was not statistically significant with IVW approach (OR = 1.20, 95% CI = 0.84-1.70, p = .32), MR-Egger regression (OR = 1.65, 95% CI = 0.19-14.43, p = .65) and weighted median approaches (OR = 1.44, 95% CI = 0.94-2.23, p = .09). However, heterogeneity was observed with MR-Egger (p = .001) and IVW (p = .001) analysis. Similar results were obtained with MR-PRESSO (global heterogeneity test p value <.01). After removing one outlier (rs9636202), with weighted median method, we found GERD increased the risk of IPF (OR 1.55, 95% CI: 1.01-2.36, p = .045) while not with the IVW (OR: 1.27, 95% CI: 0.91-1.78, p = .16) and MR-Egger method (OR: 2.01, 95% CI: 0.26-15.8, p = .51). Hence, we set a stricter instrument p value threshold to a level of <1 x 10-8, there was no statistical significance with MR estimates. Additionally, there was no directional pleiotropy observed (intercept = -0.01; SE = 0.036. p = .772). To validate causal effect of GERD on IPF, we identified three SNPs (rs79348626, rs12759463 and rs4269485) from another GWAS data that were significantly associated with GERD independently. The analysis showed no evidence of causality between GERD and IPF using the IVW method (OR = 0.91, 95% CI = 0.42-1.97, p = .814), MR-Egger regression (OR = 0.43, 95% CI = 0.06-3.07, p = .553) and weighted median approaches (OR = 0.90, 95% CI = 0.36-2.27, p = 0 0.819). Conclusions: Our analysis using MR does not support GERD could significantly increase the incidence of IPF, which suggests that treating GERD cannot reduce the risk of developing IPF.