Systemic Inflammation and Colorectal Cancer: Assessing the Role of Reverse Causality.
- 1Cancer Prevention Graduate School, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
- 2Division of Clinical Epidemiology of Early Cancer Detection, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Abstract
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.
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BibTeX
@article{safizadeh2026systemic,
title = {{Systemic Inflammation and Colorectal Cancer: Assessing the Role of Reverse Causality.}},
author = {Fatemeh Safizadeh and Tafirenyika Gwenzi and Marko Mandic and Michael Hoffmeister and Hermann Brenner},
journal = {Cancers},
year = {2026},
month = oct,
doi = {10.3390/cancers18193190},
url = {https://europepmc.org/article/MED/42882884},
note = {CC BY},
}
RIS
TY - JOUR
TI - Systemic Inflammation and Colorectal Cancer: Assessing the Role of Reverse Causality.
AU - Fatemeh Safizadeh
AU - Tafirenyika Gwenzi
AU - Marko Mandic
AU - Michael Hoffmeister
AU - Hermann Brenner
PY - 2026
DA - 2026/10/02
JO - Cancers
DO - 10.3390/cancers18193190
UR - https://europepmc.org/article/MED/42882884
AB - 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.
SN - 2072-6694
ER -