Mediation of associations between adiposity and colorectal cancer risk by inflammatory and metabolic biomarkers

Inflammation and hyperinsulinemia may drive associations between adiposity and colorectal cancer (CRC) risk, but few studies have examined this hypothesis using mediation analysis. We used inverse odds ratio weighting and logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) for estimated total effects (ORTE) of body mass index, waist circumference, and adult weight gain on CRC risk, and estimated effects operating through seven inflammatory and metabolic biomarkers (natural indirect effect; ORNIE) or through paths independent of these biomarkers (natural direct effect; ORNDE) among 209 CRC cases and 382 matched controls nested within the Health Professionals Follow‐up Study, a prospective cohort of male health professionals. A one‐interquartile range (IQR) increase in body mass index (3.6 kg/m2) was associated with an ORTE of 1.40 (95% CI: 1.13, 1.73), which decomposed into an ORNIE of 1.26 (95% CI: 0.97, 1.52) and an ORNDE of 1.11 (0.87, 1.42), with possibly stronger mediation by these biomarkers for adult weight gain (IQR = 10.4 kg; ORTE = 1.32 [95% CI: 1.06, 1.64]; ORNIE = 1.47 [95% CI: 1.01, 1.81]; ORNDE = 0.89 [95% CI: 0.72, 1.11]), but no mediation for waist circumference. Mediation appeared to be stronger for the metabolic biomarkers than the inflammatory biomarkers. Inflammatory and metabolic mechanisms may mediate associations between both body mass index and adult weight gain with CRC risk. What's new? Adiposity is one of the strongest and most consistent modifiable risk factors for colorectal cancer. Adiposity also affects insulin resistance and is associated with low‐grade chronic inflammation ‐‐ both of which have been suggested as possible mechanisms for associations between adiposity and colorectal cancer risk. Using a novel mediation analysis method, here the authors demonstrate that metabolic and inflammatory biomarkers may jointly mediate associations between both BMI and adult weight gain with colorectal cancer risk in men, with stronger results for metabolic biomarkers. The findings offer mechanistic and methodologic insights into the underlying biology of adiposity and colorectal cancer risk.