Abstract
BACKGROUND: Endometrial carcinoma (EC) remain a malignancy with incompletely understood risk factors. To address this knowledge gap, we employed mendelian randomization study to investigate potential protective and risk elements associated with endometrial cancer. METHODS: We conducted a two-sample Mendelian randomization (MR) study using genetic association data for overall EC and its subtypes from a large-scale genome-wide association study (GWAS). This GWAS encompassed 12,906 EC patients and 108,979 healthy controls. The EC cases were further categorized into 8758 endometrioid and 1230 non-endometrioid subtypes. To serve as instrumental variables, we identified independent genetic variants strongly associated with 5 lifestyle factors and 14 metabolic factors from relevant GWASs. Subsequently, we conducted univariable Mendelian randomization (MR) analyses. RESULTS: Our study revealed the relationship among EC with lifetime smoking index (OR: 1.43; 95% CI 1.05-1.96), frequency of alcohol consumption (OR:1.23; 95% CI 1.04-1.45), body mass index (BMI) (OR:1.82; 95% CI 1.64-2.01), type 2 diabetes mellitus (T2DM) (OR:1.06; 95% CI 1.00-1.12), and fasting insulin (OR:1.97; 95% CI 1.30-2.98). Conversely, inverse associations with EC were observed for education level (OR:0.72, 95% CI 0.62-0.83), moderate-level physical exercise (OR 0.35, 95% CI 0.15-0.84), and low-density lipoproteins (LDL) (OR 0.91, 95% CI 0.84-0.99). CONCLUSIONS: Our findings underscore a causal association between genetically predicted lifetime smoking index, alcohol intake frequency, BMI, T2DM, and fasting insulin with EC risk. Furthermore, our study highlights the potential protective effects of a high education level, moderate-intensity physical exercise, and LDL reduction against EC risk. This MR analysis provided valuable insights into underlying EC risk mechanisms and paved new ways for EC prevention strategies.