A Blood Metabolic Signature of a Healthy Lifestyle and Colorectal Cancer Risk: Results from Cohort and Mendelian...

Despite a healthy lifestyle being linked to reduced colorectal cancer risk, prior studies using surveys to measure lifestyle factors failed to consider potential interindividual 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 colorectal cancer risk.

Among 211,135 UK Biobank participants, we derived a healthy lifestyle score 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 HRs and 95% confidence intervals (CI) for the association of the signature with colorectal cancer 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 analysis in 78,473 colorectal cancer cases and 107,143 controls of European ancestry.

The metabolic signature, which explained 32.6% of the total variance in the healthy lifestyle score, was associated with 12% lower colorectal cancer risk (HR = 0.88; 95% CI, 0.84-0.92 per SD increase; Ptrend < 0.001). Mendelian randomization results provided strong evidence of a potential causal association of the signature with colorectal cancer (OR = 0.90; 95% CI, 0.84-0.95 per SD increase; P value < 0.001).

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

Our study further supported lifestyle modifications and identified potential targets for colorectal cancer prevention.