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

Abstract

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.

Explaining the link between adiposity and colorectal cancer risk in men and postmenopausal women in the UK Biobank: A sequential causal mediation analysis

“…95%CI, 1.14-1.73) was explained by all inflammatory (CRP, interleukin-6, tumour necrosis factor receptor 2, and macrophage inhibitory cytokine-1) and metabolic (adiponectin, C-peptide, and soluble leptin receptor (sOB-R)) biomarkers (OR NIE 1.26; 95%CI, 0.97-1.52) 38 . The authors repeated the mediation analysis separately for the two biomarker groups, assuming that the pathways were independent.…”

Importance of circulating leptin and adiponectin in the causal pathways between obesity and the development of colorectal cancer in Japanese men.

“…for metabolic biomarkers such as adiponectin, C-peptide, and soluble leptin receptors. 41 Interestingly, leptin and soluble leptin receptors may have been mediators in all three previous studies. These findings are partially consistent with our current findings, even though we were unable to compare our results with those from previous studies due to differences in the number In this study, we used a relatively new approach within the causal mediation analysis framework to estimate certain path-specific effects identified from the observed data.…”

“…Few studies have formally examined the mechanistic associations between obesity and CRC risk using mediation analysis. [38][39][40][41] Ho et al reported that leptin and insulin partially explained the association between waist circumference and the risk of CRC in a Women's…”

Adiposity and cancer: meta-analysis, mechanisms, and future perspectives

“…High fasting insulin concentrations are associated with increased risks of breast 107,108 , endometrial 102 , pancreatic 109,110 , colorectal 111 , renal 112 , gastric 113,113 and liver cancers 114,115 . In an MR mediation analysis, high fasting insulin mediated 19% (95% CI: 5-34%) of the association of obesity with endometrial cancer 102 , and observational studies have reported that high insulin may also largely mediate associations between BMI and colorectal cancer 116,117 .…”