Causal relationship between type II diabetes mellitus, metformin, insulin, gliclazide, and esophageal cancer-insights from two-sample Mendelian randomization study and meta-analysis.

BACKGROUND

Over recent decades, findings on the potential correlation between type II diabetes mellitus (T2DM) and the risk of esophageal cancer (EC) have displayed considerable heterogeneity. Furthermore, metformin has emerged as a potentially protective agent against certain site-specific malignancies. This study aims to explore the causal relationship between T2DM, medication treatments (metformin, insulin, gliclazide), and EC risk while addressing the notable variability in previous research findings.

METHODS

To elucidate the causal associations between T2DM, medication treatments, and EC, we employed a synergistic methodology that integrates the two-sample Mendelian randomization (MR) approach with meta-analysis. The genome-wide association studies (GWAS) pertaining to each exposure and EC were acquired from a publicly accessible database.

RESULTS

For MR analyses, three out of seven GWAS datasets within the T2DM cohort exhibited statistical significance. Conversely, all MR analyses yielded non-significant results in the medication cohort. Meta-analyses suggested that a genetic predisposition to T2DM correlated with a reduced risk of EC [odds ratio (OR), 0.999612; 95% confidence interval (CI): 0.999468-0.999756; P=0.01; I=0%]. Moreover, metformin intake was causally linked to a decreased prevalence of EC (OR, 0.988954; 95% CI: 0.979044-0.998963; P=0.03; I=0%), whereas neither insulin nor gliclazide manifests statistical significance.

CONCLUSIONS

Our findings indicate T2DM and metformin are causally associated with diminished risk of EC, while no causal associations exist between insulin, gliclazide, and EC.