Yuan Fangcheng, Shuai Yu, Wen Wanqing, Jia Guochong, Ruiter Rikje, Xu Shuai, Yang Yaohua, Long Jirong, Ghanbari Mohsen, Shu Xiao-Ou, Yu Danxia, Zheng Wei
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Cancer Epidemiol Biomarkers Prev. 2025 Sep 2;34(9):1566-1576. doi: 10.1158/1055-9965.EPI-25-0196.
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.
尽管健康的生活方式与降低结直肠癌风险相关，但先前使用调查来衡量生活方式因素的研究未能考虑代谢反应中潜在的个体间异质性。我们旨在将代谢特征作为对健康生活方式的代谢反应的一种衡量指标，并评估其与结直肠癌风险的关联。
在211,135名英国生物银行参与者中，我们从八个生活方式组成部分得出了一个健康生活方式评分，并应用弹性网络回归从基线时采集的血浆样本中的249种生物标志物中得出其代谢特征。使用Cox比例风险模型估计该特征与结直肠癌风险关联的风险比（HR）和95%置信区间（CI）。为了推断该特征的潜在因果关系，我们在184,765名欧洲血统的英国生物银行参与者中进行了全基因组关联研究，随后在78,473例结直肠癌病例和107,143名欧洲血统对照中进行了两样本孟德尔随机化分析。
该代谢特征解释了健康生活方式评分总方差的32.6%，与结直肠癌风险降低12%相关（每标准差增加，HR = 0.88；95% CI，0.84 - 0.92；P趋势 < 0.001）。孟德尔随机化结果提供了有力证据，表明该特征与结直肠癌存在潜在因果关联（每标准差增加，OR = 0.90；95% CI，0.84 - 0.95；P值 < 0.001）。
表征健康生活方式的代谢特征与结直肠癌风险呈负相关。构成该特征的某些生物标志物可能参与了结直肠癌发病的生活方式途径。
我们研究进一步支持了生活方式的改变，并确定了结直肠癌预防的潜在靶点。
