A blood metabolic signature of a healthy lifestyle and colorectal cancer risk: results from cohort and Mendelian randomization studies.

Background: Despite a healthy lifestyle being linked to reduced colorectal cancer (CRC) risk, prior studies using surveys to measure lifestyle factors failed to consider potential inter-individual heterogeneity in metabolic responses. We aimed to characterize a metabolic signature as a measure of metabolic responses to a healthy lifestyle and evaluate its association with CRC risk.

Methods: Among 211,135 UK Biobank participants, we derived a healthy lifestyle score (HLS) from eight lifestyle components and applied elastic net regression to derive its metabolic signature from 249 biomarkers in plasma samples collected at baseline. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of the signature with CRC risk. To infer potential causality of the signature, we conducted a genome-wide association study among 184,765 UK Biobank participants of European ancestry, followed by a two-sample Mendelian randomization (MR) analysis in 78,473 CRC cases and 107,143 controls of European ancestry.

Results: The metabolic signature, which explained 32.6% of the total variance in HLS, was associated with 12% lower CRC risk (HR=0.88; 95% CI=0.84-0.92 per standard deviation [SD] increase; Ptrend<0.001). MR results provided strong evidence for a potential causal association of the signature with CRC (odds ratio [OR]=0.90; 95% CI=0.84-0.95 per SD increase; P-value<0.001).

Conclusions: A metabolic signature characterizing a healthy lifestyle was inversely associated with CRC risk. Certain biomarkers constituting the signature may be involved in the lifestyle pathway for CRC incidence.

Impact: Our study further supported lifestyle modifications and identified potential targets for CRC prevention.