Gastroesophageal reflux disease causes an increased risk of chronic obstructive pulmonary disease: a two-sample bidirectional Mendelian randomization study

Abstract:

Objective To investigate the causal relationship between gastroesophageal reflux disease（GERD） and chronic obstructive pulmonary disease（COPD） using two-sample bidirectional Mendelian randomization（MR）.Methods Based on the pooled data from large-scale genome-wide association studies（GWAS），single nucleotide polymorphisms（SNPs） which were independent of each other and highly correlated with GERD and COPD were selected as instrumental variables. The inverse-variance weighted fixed-effects（IVW-FE） model was used as the main analysis method，while simple median，weighted median，and MR-Egger regression methods were used to validate the results and test the stability. The F-statistic，Cochran’s Q test，MR-Egger intercept test，Mendelian randomization pleiotropy residual sum and outlier（MR-PRESSO） test，and leave-one-out method were used for sensitivity analysis. The odds ratio（OR） and 95% confidence interval（CI） were used as effect sizes for the bidirectional causal relationship between GERD and COPD.Results The IVW-FE analysis showed that GERD increased the risk of COPD（OR=1.757，95%CI=1.425-2.166，P=0.000），which was confirmed by the simple median and weighted median methods. However，no causal relationship between the two factors was shown by the MR-Egger method. In the inverse MR analysis，there was no evidence of increased risk of GERD caused by COPD using IVW-FE（OR=0.999，95%CI=0.962-1.037，P=0.962）. Similarly，no association between the two factors was found using the simple median，weighted median，and MR-Egger regression methods. The F-statistic of the instrumental variable was greater than 10，which showed that there was no weak instrumental variable. The Cochran’s Q test，MR-Egger intercept test，and MR-PRESSO test did not show heterogeneity or horizontal pleiotropy between instrumental variables. The leave-one-out analyses indicated that no single SNP had a significant effect on the overall outcome.Conclusion GERD is significantly and causally associated with an increased risk of COPD. However，there is no evidence suggesting that COPD causes an increased risk of GERD.