Age- and sex-dependent associations of metabolic syndrome with colorectal cancer in the UK Biobank

BACKGROUND: The concurrent rise in metabolic syndrome (MetS) and the changing age profile of colorectal cancer (CRC) necessitates clarifying the heterogeneity in their association across demographic groups. This study aimed to define the precise age- and sex-specific associations between MetS and CRC risk, addressing a key gap to inform targeted prevention paradigms. METHODS: In this cohort study, we analysed data from UK Biobank participants aged 40-69 years (recruited 2006-2010). Participants were stratified by age (<60 or ≥60 years) and sex into four groups. Multivariable Cox proportional hazards models were used to assess the associations of MetS, the number of metabolic abnormalities, and each component with CRC incidence. RESULTS: Among 379,173 participants, 4971 developed CRC during a median follow-up of 11.8 years. MetS was most strongly associated with CRC in younger males (hazard ratio [HR] 1.31, 95% CI 1.15-1.50), significantly in older adults of both males (HR 1.18, 95% CI 1.07-1.30) and females (HR 1.18, 95% CI 1.05-1.33), but not in younger females (HR 1.05, 95% CI 0.89-1.25). Older males but not females showed increasing risks when having 3, 4, and 5 abnormalities compared to none, respectively. Beyond younger females, elevated waist circumference was the sole component consistently linked to higher risk. CONCLUSIONS: The association between MetS and CRC is strongly dependent on age and sex in White populations, with the highest risk concentrated in young and middle-aged males. These findings directly support risk-stratified prevention and provide crucial clues for investigating the underlying sex- and age-specific biological mechanisms.