Interleukin-6 and risk of colorectal cancer: results from the CLUE II cohort and a meta-analysis of prospective studies

Abstract

Purpose The association between prediagnostic inter-leukin-6 (IL-6) concentrations and risk of colorectal cancer was evaluated in a nested case–control study and a meta-analysis of prospective studies. Methods Colorectal cancer cases (n = 173) and matched controls (n = 345) were identified between 1989 and 2000 among participants in the CLUE II cohort of Washington Country, Maryland. Matched odds ratios and the corresponding 95 % confidence intervals (CIs) were estimated using conditional logistic regression models. Results Participants in the highest third of plasma IL-6 concentration had a 2.48 times higher risk of colon cancer compared to participants in the bottom third (95 % CI 1.26–4.87; p-trend 0.02) after multivariate adjustment. This association did not differ according to the stage of disease, age, sex, or other potential modifying variables and remained statistically significant after adjustment for C-reactive protein concentrations. No statistically significant association was observed for rectal cancer risk. The meta-analysis of six prospective studies yielded an increased but borderline statistically significant risk of colon cancer per 1 U increase in naturally logarithm-transformed IL-6 (summary RR 1.22; 95 % CI 1.00–1.49; I2 46 %). An inverse association was noted for rectal cancer (RR 0.69; 95 % CI 0.54–0.88; I2 0 %), but there was evidence for small-study effects (p 0.02). Conclusion Our findings provide support for a modest positive association between IL-6 concentrations and colon cancer risk. More work is needed to determine whether IL-6 is a valid marker of colorectal inflammation and whether such inflammation contributes to colon and rectal cancer risk.

Inflammatory biomarkers, aspirin, and risk of colorectal cancer: Findings from the physicians’ health study

“…The totality of the current evidence, as summarized in previous meta-analyses, suggests that CRP is weakly associated with an increased risk for colorectal cancer 23,24 . Our null association between plasma IL-6 level and colorectal cancer risk was consistent with conclusions from most previous published prospective studies 9,12,13,25 , and meta-analyses 24,25 . In one study, IL-6 levels were associated with colorectal cancer risk, but the association did not remain significant after further adjustment for insulin 20 .…”

“…Of note, in the Health Professionals Follow-up Study, there was a significant association of IL-6 with colorectal cancer among lean men17, which was not observed in this study. Lastly, data from the prospective CLUE II cohort suggest that there is a significant association between IL-6 levels and risk of colon cancer 25 . While our study did not confirm this finding, more prospective research is required to determine whether plasma IL-6 levels are associated with colon cancer risk.…”

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

“…Results for mediation by inflammatory biomarkers were weaker for all analyses, despite the fact that adiposity is associated with low‐grade systemic inflammation, and that systemic inflammation has been linked to CRC risk, though inconsistently. Several studies, have observed null or weak associations between many of these circulating inflammatory biomarkers and CRC risk, while other studies have observed positive associations . Notably, in exploratory subgroup analyses, we observed qualitatively stronger mediation by the biomarkers among nonusers of NSAIDs/aspirin compared to regular users, although these analyses were low in power.…”

Polymorphisms in genes related to inflammation and obesity and colorectal adenoma risk

“…Interleukin‐6 (IL‐6) is a cytokine involved in many proinflammatory pathways of the immune response . We reported a positive association between plasma IL‐6 concentration and risk of colon cancer in this cohort, and presented a meta‐analysis of six prospective studies that provided support for a modest positive association between IL‐6 concentrations and colon cancer risk . In the present study, we identified a borderline inverse association between a candidate SNP in IL6 (rs1800797) and adenomas and, among leaner individuals only, a positive association between a different candidate SNP in IL6 (rs1800796) and adenomas.…”