Impact of glycemic traits, type 2 diabetes and metformin use on breast and prostate cancer risk: a Mendelian randomization study
Bibliographic record
Abstract
Objectives Observational studies suggest glycemic traits and type 2 diabetes are positively associated, and metformin inversely associated with breast and prostate cancer risk. However, observational studies are susceptible to unmeasured confounding while studies of metformin use are also vulnerable to immortal time bias. The use of Mendelian randomization may reduce confounding due to random allocation of relevant genetic markers at birth, and may reduce immortal time bias (for metformin-related variants analysis) since the start of exposure is at birth. Research design and methods We identified strong genetic predictors of fasting glucose, glycated hemoglobin, and type 2 diabetes from the Meta-Analyses of Glucose and Insulin-related traits Consortium and Diabetes Genetics Replication And Meta-analysis Consortium (n=140 595 for glucose; n=123 665 for HbA1c; n=898 130 for type 2 diabetes) and of AMPK-instrumented HbA1c reduction as a proxy of metformin and applied them to large genome-wide association studies of breast cancer (Breast Cancer Association Consortium; BCAC) and prostate cancer (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome; PRACTICAL). We used inverse variance weighting to obtain estimates. Sensitivity analyses included use of MR-Egger, weighted median, exclusion of pleiotropic instruments, and validation using UK Biobank (breast cancer only). Results There was no association of fasting glucose (OR 1.03 per mmol/L, 95% CI 0.85 to 1.25), HbA1c (OR 1.02 per %, 95% CI 0.73 to 1.45), or type 2 diabetes (OR 0.98 per log odds, 95% CI 0.95 to 1.01) with breast cancer in BCAC, with similar findings from UK Biobank. There was no association of fasting glucose (OR 0.93 per mmol/L, 95% CI 0.73 to 1.17), HbA1c (OR 0.90 per %, 95% CI 0.58 to 1.40) or type 2 diabetes (OR 1.02 per log odds, 95% CI 0.97 to 1.07) with prostate cancer in PRACTICAL. No strong evidence was observed for AMPK-instrumented HbA1c reduction on cancer risk. Conclusion Glycemic traits and type 2 diabetes unlikely cause breast and prostate cancer. Whether metformin can be repurposed for cancer prevention remains unclear.
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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 | 0.034 | 0.081 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.007 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.002 | 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".