PO.PS01.01 · 人群科学
循环脂质和胆汁酸代谢物作为结直肠癌风险的预测因子:一项多队列代谢组学荟萃分析
Circulating lipid and bile acid metabolites as predictors of colorectal cancer risk: A multi-cohort metabolomics meta-analysis
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摘要 Abstract
中文摘要
背景:代谢失调已被认为与结直肠癌(CRC)的发生有关,但尚未得到充分表征。我们开展了一项大规模代谢组学荟萃分析,以识别在异质性人群中与未来CRC风险相关的循环代谢物。
方法:我们协调整合了来自七个前瞻性队列的诊断前代谢组学和协变量数据:癌症预防研究II营养队列(CPS-II)、前列腺癌、肺癌、结直肠癌和卵巢癌筛查试验(PLCO)、妇女健康倡议营养代谢组学研究(WoMIN)、护士健康研究(NHS)、卫生专业人员随访研究(HPFS)、上海女性健康研究(SWHS)和上海男性健康研究(SMHS)。我们使用多变量逻辑回归,应用固定效应荟萃分析评估1,039种协调后代谢物与CRC风险之间的关联,并对体重指数和其他协变量进行校正。
结果:在七个队列中(N = 3,779,50%为病例),参与者以女性为主(59.5%),中位年龄为68岁(IQR 62-73),中位BMI为25.0 kg/m²(IQR 23.0-28.0)。14种代谢物与CRC风险显著相关(FDR < 0.05)。在富含多不饱和脂肪酸的磷脂和醚脂中观察到负相关(如PE(20:0/18:2)、PE(22:6/P-18:1)、PC(22:6/18:0);OR范围0.47-0.63,p值范围6.2E-04至6.8E-13)。正相关包括单酰基甘油(MG(18:3))、胆汁酸(如甘氨鹅脱氧胆酸)和外源性化合物(如N-十一烷基苯磺酸)。异质性较低(显著代谢物间的平均I²约为15%),且方向在各研究间一致。
结论:这项多队列分析将脂质代谢和胆汁酸信号传导确定为CRC病因学中的关键通路之一,且独立于肥胖。与多不饱和脂质种类的负相关以及与胆汁酸和外源性物质的正相关表明,膜脂质重塑、肠-肝轴扰动和环境暴露可能在CRC发生中发挥机制性作用。在欧洲癌症与营养前瞻性调查(EPIC)队列中使用非靶向代谢组学数据进行的外部验证正在进行中,将为这些代谢物作为CRC风险分层和预防生物标志物的效用提供参考。
查看英文原文 English abstract
Background: Metabolic dysregulation has been implicated in colorectal cancer (CRC) development but not fully characterized. We conducted a large-scale metabolomics meta-analysis to identify circulating metabolites associated with future CRC risk across heterogeneous populations.
Methods: We harmonized pre-diagnostic metabolomic and covariate data from seven prospective cohorts: the Cancer Prevention Study II Nutrition Cohort (CPS-II), the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), the Women's Health Initiative Metabolomics in Nutrition Study (WoMIN), the Nurses' Health Study (NHS), the Health Professionals Follow-up Study (HPFS), the Shanghai Women's Health Study (SWHS), and the Shanghai Men's Health Study (SMHS). Using multivariable logistic regression, we applied fixed-effects meta-analysis to evaluate associations between 1,039 harmonized metabolites and CRC risk, adjusting for body mass index and other covariates.
Results: Across seven cohorts (N = 3,779, 50% cases), participants were predominantly female (59.5%), with a median age of 68 years (IQR 62-73) and median BMI of 25.0 kg/m² (IQR 23.0-28.0). Fourteen metabolites were significantly associated with CRC risk (FDR < 0.05). Inverse associations were observed for phospholipids and ether lipids enriched in polyunsaturated fatty acids (e.g., PE(20:0/18:2), PE(22:6/P-18:1), PC(22:6/18:0); OR range 0.47-0.63, p-value range 6.2E-04 to 6.8E-13). Positive associations included monoacylglycerols (MG(18:3)), bile acids (e.g., glycochenodeoxycholate), and xenobiotic compounds (e.g., N-undecylbenzenesulfonic acid). Heterogeneity was low (mean I² across the significant metabolites was ~ 15%), and directionality was consistent across studies.
Conclusions: This multi-cohort analysis identified lipid metabolism and bile acid signaling as key pathways in CRC etiology, among others, independent of adiposity. The inverse associations with polyunsaturated lipid species and the positive association with bile acids and xenobiotics suggest that membrane lipid remodeling, gut-liver axis perturbations, and environmental exposures may play mechanistic roles in CRC development. Ongoing external validation in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort using untargeted metabolomic data will inform the utility of these metabolites as biomarkers for CRC risk stratification and prevention.
利益披露 Disclosure
M. Playdon, None..
E. Braun, None..
K. Santucci, None..
M. Gunter, None.