Causal relationship between lung diseases and risk of esophageal cancer: insights from Mendelian randomization

Abstract

Background: An increasing number of cohort studies have indicated a correlation between lung diseases and esophageal cancer, but the exact causal relationship has not been definitively established. Therefore, the objective of this study is to assess the causal relationship between lung diseases and esophageal cancer.

Methods: Single-nucleotide polymorphisms (SNPs) related to lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and idiopathic pulmonary fibrosis (IPF), along with outcomes data on esophageal cancer, were extracted from public genome-wide association studies (GWAS). A two-sample Mendelian randomization (MR) analysis was then performed using publicly available GWAS data to investigate the potential causal relationship. The effect estimates were primarily calculated using the fixed-effects inverse-variance-weighted method.

Results: Totally, 81 SNPs related to asthma among 218,792 participants in GWAS. Based on the primary causal effects model using MR analyses with the inverse variance weighted (IVW) method, asthma was demonstrated a significantly related to the risk of esophageal cancer (OR 1.0006; 95% CI 1.0003-1.0010, p = 0.001), while COPD (OR 1.0306; 95% CI 0.9504-1.1176, p = 0.466), lung cancer (OR 1.0003, 95% CI 0.9998-1.0008, p = 0.305), as well as IPF (OR 0.9999, 95% CI 0.9998-1.0000, p = 0.147), showed no significant correlation with esophageal cancer.

Conclusions: The two-sample MR analysis conducted in this study revealed a positive causal relationship between asthma and esophageal cancer. In contrast, esophageal cancer demonstrated no significant correlation with COPD, lung cancer, or IPF. Further large-sample prospective studies are needed to validate these findings and to provide appropriate recommendations regarding esophageal cancer screening among patients with asthma.

Keywords: Asthma; Causal association; Esophageal cancer; Lung diseases; Mendelian randomization.

Fig. 1

Three key assumptions of the Mendelian randomization study. (A) SNPs are strongly associated with asthma, COPD, lung cancer and IPF; (B) SNPs are independent of confounders; (C) SNPs must only affect esophageal cancer via asthma, COPD, lung cancer and IPF. SNP: single-nucleotide polymorphism. COPD: chronic obstructive pulmonary disease; IPF: idiopathic pulmonary fibrosis

Fig. 2

Associations of genetically predicted asthma, COPD, lung cancer and IPF with esophageal cancer. CI, confidence interval; OR, odds ratio; COPD: chronic obstructive pulmonary disease; IPF: idiopathic pulmonary fibrosis

Fig. 3

Forest plot of the association of asthma and esophageal cancer

Fig. 4

Scatter plot of the association of asthma and esophageal cancer