Comprehensive analysis of the impact of circulating metabolites on the risk of endometrial cancer: a Mendelian randomization study

Background: Endometrial cancer (EC) is the predominant gynecological malignancy in developed countries and is closely associated with metabolic syndrome. However, the underlying pathogenic mechanisms and the impact of serum circulating metabolites (CMs) on EC risk remain largely unexplored. Methods: To elucidate potential associations between CMs and EC, a two-sample Mendelian randomization (MR) study was conducted. The study utilized summary genome-wide association study (GWAS) data labeled as ebi-a-GCST006464, serving as the outcome dataset, which included data from 12,906 cases and 108,979 controls, all of European descent. Genetic predictors associated with CMs were sourced from three metabolite GWAS datasets compiled by Shin, Kettunen, and Borges. Results: The MR analyses revealed 36 associations between CMs and EC that passed a nominal p-value significance threshold (p-value range: 0.003–0.0492). However, upon multiple testing correction, none of the CMs remained significantly associated with EC. Subgroup analysis found 27 associations between CMs and endometrioid EC passed a nominal p-value significance threshold (p-value range: 5.69 × 10−6–0.0499). Notably, the associations for 4-androsten-3beta,17beta-diol disulfate 2 and Hexadecanedioate survived multiple testing corrections (False Discovery Rate (FDR) = 0.0015 and 0.0422, respectively). Concurrently, 78 associations between CMs and non-endometrioid EC passed a nominal p-value significance threshold (p-value range: 0.0003–0.4997). Furthermore, 23 associations between CMs (all belonging to lipometabolomics) and non-endometrioid EC survived multiple testing corrections (FDR value range: 0.0435–0.0486). Conclusions: This analysis has identified specific CMs potentially associated with EC, especially in non-endometrioid EC. The results offer new evidence of the association between CMs and EC, including its risk factors. This information may guide the development of metabolite-based interventions for EC and its risk factors in forthcoming clinical trials and can also act as candidate targets for further mechanism exploration and drug selection.

Circulating metabolites; Mendelian randomization; Endometrial cancer; Endometrioid histology; Non-endometrioid histology; Genome-wide association studies

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