Objective To investigate the causal associations between components of metabolic syndrome (MetS) and endometrial carcinoma using Mendelian randomization (MR).

Methods Data mining of the Genome-Wide Association Studies (GWAS) database was performed, with the exposure factors being MetS components (lipids, blood pressure, blood glucose, and obesity) and the outcome factor being endometrial carcinoma. MR analyses were performed with the help of regression models, including MR-Egger method, weighted median method, and inverse variance weighted (IVW) method, and the causal relationship between MetS components and endometrial carcinoma was evaluated by odds ratio (OR). Reverse MR analysis was performed for the MetS components found to have a causal relationship with endometrial carcinoma in the forward MR analysis.

Results After applying Benjamini-Hochberg correction, IVW results showed a causal relationship between multiple MetS components (obesity, lipids, blood pressure, and blood glucose) and endometrial carcinoma. Specifically, the three components of obesity, including body mass index, overweight, and percentage of body fat, were causally associated with an increased risk of endometrial carcinoma (P<0.001, OR>1). In blood lipids, high cholesterol levels (P<0.001, OR<1), high triglyceride levels, and high phospholipid levels were causally associated with a reduced risk of endometrial carcinoma (P<0.05, OR<1). Regarding blood pressure, heart disease, atherosclerosis, and stroke were causally associated with a reduced risk of endometrial carcinoma (P<0.05, OR<1). Regarding blood glucose, low fasting insulin levels, type 1 diabetes mellitus, insulin resistance, and high glycated hemoglobin levels were causally associated with a reduced risk of endometrial carcinoma (P<0.05, OR<1), while type 2 diabetes mellitus and high fasting insulin levels were causally associated with an increased risk of endometrial carcinoma (P<0.05, OR>1). Reverse MR analysis did not produce any evidence for a reverse causality between the above positive MetS components and endometrial carcinoma.

Conclusion The MR study suggests that obesity and type 2 diabetes mellitus are risk factors for endometrial carcinoma, while other MetS components, including hyperlipidemia, cardiovascular diseases, insulin resistance, and complications of diabetes mellitus, are protective factors for endometrial carcinoma. Further research is needed to clarify the association between MetS and endometrial carcinoma and to further explore the underlying mechanisms involved.