The Causal Relationship Between Gastroesophageal Reflux Disease and Chronic Obstructive Pulmonary Disease: A Bidirectional Two-Sample Mendelian Randomization Study

Abstract

Background

Gastroesophageal reflux disease (GERD) and Chronic Obstructive Pulmonary Disease (COPD) often coexist and have been associated in observational studies. However, the real potential causal relationship between GERD and COPD is unknown and not well established.

Methods

In this study, we conducted a bidirectional two-sample Mendelian randomization(MR) to estimate whether GERD and COPD are causal. The GERD genetic data is from summary level data of a genome-wide association (GWAS) meta-analysis (Ncases = 71,522, Ncontrol=26,079). The COPD GWAS are available from the FinnGen (Ncases=16,410, Ncontrol=283,589). MR-Egger regression, Weighted Median, and Inverse-variance weighted (IVW) were used for MR analysis from the R package “TwoSampleMR”, and IVW was the dominant estimation method. Additionally, the MR pleiotropy residual sum and outlier (MR-PRESSO), Cochran Q statistic, and leave-one-out analysis were used to detect and correct for the effect of heterogeneity and horizontal pleiotropy.

Results

MR analysis indicated that GERD was causally associated with an increased risk of COPD (IVW odds ratio (OR): 1.3760, 95% confidence interval (CI): 1.1565–1.6371, P=0.0003), and vice versa (IVW OR: 1.1728, 95% CI:1.0613–1.2961, P=0.0018). The analyses did not reveal any pleiotropy or heterogeneity.

Conclusion

Our study revealed possible evidence for a bidirectional causal relationship between GERD and COPD. Implementing screening and preventive strategies for GERD in individuals with COPD, and vice versa, will be crucial in future healthcare management. Further studies are needed to elucidate the mechanisms underlying the causal relationship between GERD and COPD.

Keywords:

• human genetics
• Mendelian randomization
• gastroesophageal reflux disease
• causal relationship
• chronic obstructive pulmonary disease

Abbreviations

GERD, Gastroesophageal reflux disease; COPD, Chronic Obstructive Pulmonary Disease; GWAS, genome-wide association study; MR, Mendelian randomization; IVW, Inverse-variance weighted; MR-PRESSO, MR pleiotropy residual sum and outlier; OR, odds ratio; CI, confidence interval; CRD, chronic respiratory disease; IVs, instrumental variables; SNPs, single nuclear polymorphisms; LD, linkage disequilibrium; SE, standard error; LES, lower esophageal sphincter; ECM, extracellular matrix; RBPs, RNA-binding proteins; EMT, epithelial-mesenchymal transition; TJ, tight junction.

Data Sharing Statement

All data generated or analysed during this study are included in this published article and its Supplementary Information Files.

Ethics Approval and Consent to Participate

This study was approved by the Ethics Committee of the Affiliated Hospital of Southwest Medical University. Because of this study relied on the publicly available summary data from the GWAS study, the requirement for informed consent was waived.

Acknowledgments

We want to acknowledge the participants and investigators of the FinnGen study and the participants of all GWAS cohorts included in the present work.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no competing interests.

Additional information

Funding

There is no funding to report.