Systemic Inflammation and Colorectal Cancer: Assessing the Role of Reverse Causality

Background/Objectives: Prospective studies have reported associations between systemic inflammatory biomarkers and colorectal cancer (CRC) risk, but whether these reflect a causal role of inflammation or responses to preclinical disease remains uncertain. Methods: Using data from 383,850 UK Biobank participants (aged 40-69 years; recruited 2006-2010), we investigated potential reverse causality by assessing these associations according to time since biomarker assessment. Baseline systemic inflammatory markers, including C-reactive protein (CRP), albumin, and blood cell-derived ratios, were assessed. Multivariable Cox models estimated associations with CRC risk across predefined follow-up intervals. Results: Over a median follow-up of 11.8 years, 4996 participants developed CRC. Inflammatory biomarkers were associated with increased CRC risk, particularly during the early follow-up. Associations weakened substantially or disappeared when early follow-up was excluded. For example, CRP was associated with a 3.03-fold higher CRC risk (highest vs. lowest quartile; 95% CI: 2.06-4.45) within the 0-1-year interval, while no association was observed during the 3-5, 6-8, or >8-year intervals. Across complete follow-up, the association remained statistically significant but much weaker (HR: 1.17; 95% CI: 1.07-1.28). Similar patterns were observed for most other biomarkers, except the platelet-to-neutrophil ratio. Conclusions: Our results suggest that the associations between inflammatory biomarkers and CRC risk may partly reflect reverse causality arising from preclinical disease.