Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis
Main finding · Prostate cancerResult — go to the resultOdds ratio 1.75 95% CI 1.07–2.85Authors' conclusion
Our drug target MR analyses did not find consistent evidence to support an association of genetically proxied PPARG, ABCC8 or GLP1R perturbation with breast, colorectal, prostate or overall cancer risk. Further evaluation of these drug targets using alternative molecular epidemiological approaches may help to further corroborate the findings presented in this analysis.
Study context
- Population
- Instruments from T2D genome-wide association study (GWAS) in Million Veteran Program (148,726 cases, 965,732 controls); cancer GWAS consortia: breast (122,977 cases, 105,974 controls), colorectal (58,221 cases, 67,694 controls), prostate (79,148 cases, 61,106 controls), overall cancer (27,483 cases, 372,016 controls)
- Comparison
- Genetically proxied PPARG, ABCC8 or GLP1R perturbation and cancer risk
- Outcome
- Risk of breast, colorectal, prostate and overall cancer
Methodological detailsdrug target Mendelian randomisation, inverse-variance weighted random-effects models, co-localisation analysis, Bonferroni correction
- Drug target Mendelian randomisation
- Inverse-variance weighted random-effects models
- Co-localisation analysis
- Bonferroni correction
Main finding
Prostate cancer
Odds ratio
1.75
95% CI 1.07–2.85
P = 0.02
PPARG
OR 1.75 (95% CI 1.07–2.85); P = 0.02
Per perturbation equivalent to 1 unit decrease, as printed
As reported in the abstract
Further findings
Oestrogen receptor-positive breast cancer (histological subtype-stratified)
| OR (95% CI) | P value | ||
|---|---|---|---|
| PPARGWeak evidence | 0.57 (0.38–0.85) | P = 6.45×10-3 | |
| 0.20.5125Odds ratio (log scale) |
Co-localisation in PPARG locus
- Little evidence of shared causal variants for T2D liability and cancer endpoints; likely underpowered
Original publication
Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis. Diabetologia. Published 12 May 2023. doi:10.
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