| Summary: | Background: The roles of obesity-related biomarkers and their molecular pathways in the development of postmenopausal colorectal cancer (CRC) have been inconclusive. We examined insulin resistance (IR) as a major hormonal pathway mediating the association between obesity and CRC risk in a Mendelian randomization (MR) framework.Methods: We performed MR analysis using individual-level data of 11,078 non-Hispanic white postmenopausal women from our earlier genome-wide association study. We identified four independent single-nucleotide polymorphisms associated with fasting glucose (FG), three with fasting insulin (FI), and six with homeostatic model assessment–IR (HOMA-IR), which were not associated with obesity. We estimated hazard ratios (HRs) for CRC by adjusting for potential confounding factors plus genetic principal components.Results: Overall, we observed no direct association between combined 13 IR genetic instruments and CRC risk (HR = 0.96, 95% confidence interval [CI]: 0.78–1.17). In phenotypic analysis, genetically raised HOMA-IR exhibited its effects on the increased risk and FG and FI on the reduced risk for CRC, but with a lack of statistical power. Subgroup analyses by physical activity level and dietary fat intake with combined phenotypes showed that genetically determined IR was associated with reduced CRC risk in both physical activity-stratified (single contributor: MTRR rs722025; HR = 0.12, 95% CI: 0.02–0.62) and high-fat diet subgroups (main contributor: G6PC2 rs560887; HR = 0.59, 95% CI: 0.37–0.94).Conclusions: Complex evidence was observed for a potential causal association between IR and CRC risk. Our findings may provide an additional value of intervention trials to lower IR and reduce CRC risk.
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