Abstract
BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC), which exhibits differential clinical, pathological, and molecular features compared to late-onset CRC (LOCRC), is rising globally. The potential differential effects of blood glucose on EOCRC compared to LOCRC have not been investigated. METHODS: This study analyzed 374,568 participants from the UK Biobank cohort and 172,809 participants from the Kailuan cohort. The linear associations between blood glucose and EOCRC/LOCRC were estimated using Cox regression models. Restricted cubic spline (RCS) analysis and non-linear Mendelian randomization (MR) analysis using a 70-SNPs genetic instrument for fasting glucose were used to explore the potential non-linear associations. RESULTS: Participants in the highest quintile of blood glucose had higher overall CRC risk compared to the lowest quintile (HR = 1.10 in the UK Biobank cohort, 95% CI: 1.01-1.21, P-trend = 0.012; HR = 1.23 in the Kailuan cohort, 95% CI: 1.01-1.51, P-trend = 0.036). Elevated glucose (>7.0 mmol/L) was more strongly associated with increased risk of EOCRC (HR = 1.61, 95% CI: 1.07-2.44) than with LOCRC (HR = 1.14, 95% CI: 1.02-1.27) in the UK Biobank cohort (P-heterogeneity = 0.014). Elevated glucose (>7.0 mmol/L) was associated with increased risk of LOCRC (HR = 1.25, 95% CI: 1.04-1.65) in the Kailuan cohort as well. There was no evidence for non-linear associations between blood glucose and risks of EOCRC/LOCRC. CONCLUSIONS: This study showed a positive association between blood glucose and CRC risk in a dose-response manner, particularly for EOCRC, suggesting that tighter glucose control should be a priority for younger age groups.