Exploring significant gender disparities in esophageal cancer risk: Insights from Mendelian randomization analysis and global burden of disease data.

Esophageal cancer (EC) is responsible for approximately 508,000 deaths worldwide each year. Emerging evidence suggests significant gender disparities in EC-related mortality. This study aims to explore the underlying causes of these differences. In this study, global mortality rates of EC were obtained from the global burden of disease database. Several factors strongly associated with EC risk were identified and treated as exposures. Mendelian randomization analysis was then conducted to evaluate the potential causal relationships between EC risk and testosterone levels (TLs), body mass index, smoking, alcohol consumption, red meat intake, and vegetable consumption. The results showed that higher TLs (P = .03; beta = 0.07; 95% confidence interval, 0.006-0.13) and smoking (P = .03; beta = 0.39; 95% confidence interval, 0.02-0.78) were significantly and positively associated with an increased risk of EC. No causal associations were observed between EC risk and the other investigated factors. Survival analysis revealed that PTEN and PIK3CA proteins had no statistically significant impact on the survival of EC patients (PTEN: Log-rank P = .89, HR = 1.1; PIK3CA: Log-rank P = .97, HR = 0.99). Meanwhile, TP53 protein suggested a potential adverse effect on survival (Log-rank P = .057, HR = 2.5). Significant gender disparities in the risk of EC may be attributed to the direct causal effects of smoking and elevated TLs in males. In contrast, factors such as alcohol consumption, body mass index, and dietary habits do not appear to have a significant impact on EC risk. It was also observed that the causal relationship between TLs and the risk of EC may be mediated by the TP53 protein.