Metabolic syndrome and cancer risk: A bidirectional two-sample Mendelian randomization study

Emerging evidence suggests that metabolic syndrome (MetS) contributes to cancer development, but the causal relationship remains unclear. This study aimed to explore the potential causal associations between MetS and 50 types of cancer (including the main cancer subtypes) using bidirectional Mendelian randomization (MR) analysis.

Genome-wide association study (GWAS) data were downloaded from the IEU-GWAS database and CNCR-CTGLAB. We investigated the causal associations between MetS and cancer via the inverse variance-weighted (IVW) method. We used sensitivity analyses, including Cochran's Q, MR-PRESSO, and MR-Egger intercept tests, to verify the reliability of the MR results. The P-value of the IVW analysis was adjusted for the false discovery rate (FDR) to avoid false-positive results.

The results of the IVW analysis revealed that genetically predicted MetS was positively associated with an increased risk of 11 types of cancers (P-FDR < 0.05, odds ratio [OR] = 1.23-3.01), including squamous cell lung cancer, lung cancer, endometrial cancer, endometrial cancer (endometrioid histology), endometrial cancer (non-endometrioid histology), rectal cancer, hepatic cancer, colorectal cancer, non-follicular lymphoma cancer, primary lymphoid and hematopoietic malignant neoplasm cancer, and thyroid cancer. Genetically predicted MetS was negatively associated with the risk of prostate cancer (P-FDR < 0.05, OR = 0.87). The sensitivity analyses revealed no heterogeneity or horizontal pleiotropy (P > 0.05) in the MR Egger intercept and MR-PRESSO tests, confirming the robustness of the results. Moreover, there were no reverse causalities between these cancers and MetS.

Our study revealed a positive causal relationship between genetically predicted MetS and lung cancer, lung squamous cell carcinoma, endometrial cancer, colorectal cancer, hepatic cancer, non-follicular lymphoma cancer, primary lymphoid and hematopoietic malignant neoplasm cancer, and thyroid cancer, and a negative causal relationship between genetically predicted MetS and prostate cancer, which provides important insights into the cancer prevention, treatment, and long-term health management of MetS.