Abstract
BACKGROUND: Esophageal cancer (EC), recognized for its aggressive nature, ranks as the sixth leading cause of cancer-associated mortality globally. The incidence of EC has been suggested to link with lifestyle, obesity, and glycemic traits; however, the causality of this association remains uncertain. Consequently, our study aims to elucidate the causal connections between modifiable risk factors and EC. METHOD: We adopted single nucleotide polymorphisms (SNPs) as genetic instrumental variables and conducted a two-sample Mendelian randomization (MR) analysis to estimate the causal influence of 14 amendable risk factors on EC, incorporating 740 cases and 372,016 controls. RESULTS: The data revealed a significant association of coffee intake (OR = 1.003, P = 0.046), smoking (OR = 1.008, P = 0.001), and Body Mass Index (BMI) (OR = 1.001, P = 0.002) with an increased risk of EC. Conversely, type 2 diabetes (OR = 0.999, P = 0.003), education duration (OR = 0.999, P = 0.012), and Low-Density Lipoprotein Cholesterol (LDL-C) (OR = 0.999, P = 0.011) were correlated with a reduced risk of EC. CONCLUSIONS: Our findings suggest that coffee intake, smoking, and BMI potentially contribute as risk factors in the pathogenesis of EC, whereas type 2 diabetes, duration of education, and LDL-C may function as protective elements against the development of this malignancy.