Mendelian Randomization Study: Genetic Prediction of Blood Metabolites and the Risk of Endometrial Cancer

Abstract Background: Metabolic dysregulation is a hallmark of cancer. However, evidence of a causal relationship between circulating metabolites and the promotion or prevention of colorectal cancer (CRC) is still lacking. We conducted a two-sample Mendelian Randomization (MR) analysis to assess the causal relationship between 1,400 genetically proxied blood metabolites and endometrial cancer. Methods: We extracted metabolite level data from 8,299 participants in the Canadian Longitudinal Study on Aging (CLSA) and conducted a genome-wide association study (GWAS). This study involved 1,091 metabolites and 309 metabolite ratios. We utilized the ebi-a-GCST006464 dataset from the GWAS Catalog database for endometrial cancer. This dataset covered the European population, with 12,906 cases of endometrial cancer and 108,979 controls for preliminary analysis. The primary method for causal analysis was the Inverse Variance Weighted (IVW) method, supplemented by M-R-Egger and weighted median analysis. To validate the robustness, heterogeneity, and pleiotropy of the results, we conducted comprehensive sensitivity analyses, including the Cochran Q test, MR-Egger intercept test, radial MR, and leave-one-out analysis. For the final identification of metabolites, we also performed linkage disequilibrium score regression and colocalization analysis. Results: The results of this study indicated significant associations between nine metabolites and endometrial cancer. These include: 5alpha-androstan-3alpha,17beta-diol monosulfate (1) levels (Odds Ratio [OR] 1.15, 95% Confidence Interval [CI]: 1.09-1.20, p=1.34×10−8), 5alpha-androstan-3beta,17beta-diol monosulfate (2) levels (OR 1.18, 95% CI: 1.08-1.29, p=6.46×10−7), Androstenediol (3beta,17beta) disulfate (1) levels (OR 1.23, 95% CI: 1.12-1.36, p=3.01×10−5), Hexadecanedioate (C16-DC) levels (OR 1.12, 95% CI: 1.06-1.19, p=8.43×10−5), 1-linoleoyl-GPG (18:2) levels (OR 1.13, 95% CI: 1.06-1.21, p=0.0001), Adenosine 5'-diphosphate (ADP) to pantothenate ratio (OR 1.18, 95% CI: 1.08-1.29, p=0.0001), Octadecenedioylcarnitine (C18:1-DC) levels (OR 1.11, 95% CI: 1.05-1.17, p=0.0001), Glutarate (C5-DC) levels (OR 1.18, 95% CI: 1.08-1.28, p=0.0003), X-22509 levels (OR 1.15, 95% CI: 1.06-1.24, p=0.0003). Conclusion: The results of this study reveal potential causal relationships between nine circulating metabolites and endometrial cancer, offering new insights into the biological mechanisms of endometrial cancer. These findings, derived from integrating genomics and metabolomics approaches, not only enhance our understanding of the pathogenesis of endometrial cancer but also have significant implications for the screening, prevention, and treatment strategies of endometrial cancer.