Mendelian Randomization Study: Genetic Prediction of Blood Metabolites and the Risk of Endometrial Cancer
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.021 | 0.046 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.003 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".