代谢风险因素的代谢物特征及其纵向变化
Metabolite Signatures of Metabolic Risk Factors and their Longitudinal Changes.
作者信息
Yin Xiaoyan, Subramanian Subha, Willinger Christine M, Chen George, Juhasz Peter, Courchesne Paul, Chen Brian H, Li Xiaohang, Hwang Shih-Jen, Fox Caroline S, O'Donnell Christopher J, Muntendam Pieter, Fuster Valentin, Bobeldijk-Pastorova Ivana, Sookoian Silvia C, Pirola Carlos J, Gordon Neal, Adourian Aram, Larson Martin G, Levy Daniel
机构信息
Framingham Heart Study (X.Y., S.S., C.M.W., G.C., P.C., B.H.C., S.-J.H., C.S.F., C.J.O., M.G.L., D.L.), Framingham, Massachusetts 01702; Boston University Department of Mathematics and School of Public Health (X.Y., M.G.L.), Boston, Massachusetts 02118; Population Sciences Branch (S.S., C.M.W., G.C., P.C., B.H.C., S.-J.H., C.S.F., C.J.O., D.L.), Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892; BG Medicine, Inc (P.J., X.L., P.M., N.G., A.A.), Waltham, Massachusetts 02451; Department of Medicine (C.S.F.), Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; Department of Medicine (C.J.O.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; Mount Sinai School of Medicine (V.F.), New York, New York 10029; Centro Nacional de Investigaciones Cardiovasculares (V.F.), 28029 Madrid, Spain; TNO Triskelion BV, Inc (I.B.-P.), 3704 HE Zeist, The Netherlands; Institute of Medical Research A Lanari-IDIM, University of Buenos Aires (S.C.S., C.J.P.), National Scientific and Technical Research Council, Ciudad Autónoma de Buenos Aires C11428, Argentina; and Boston University School of Medicine (D.L.), Boston, Massachusetts 02118.
出版信息
J Clin Endocrinol Metab. 2016 Apr;101(4):1779-89. doi: 10.1210/jc.2015-2555. Epub 2016 Feb 23.
CONTEXT
Metabolic dysregulation underlies key metabolic risk factors—obesity, dyslipidemia, and dysglycemia.
OBJECTIVE
To uncover mechanistic links between metabolomic dysregulation and metabolic risk by testing metabolite associations with risk factors cross-sectionally and with risk factor changes over time.
DESIGN
Cross-sectional—discovery samples (n = 650; age, 36–69 years) from the Framingham Heart Study (FHS) and replication samples (n = 670; age, 61–76 years) from the BioImage Study, both following a factorial design sampled from high vs low strata of body mass index, lipids, and glucose. Longitudinal—FHS participants (n = 554) with 5–7 years of follow-up for risk factor changes.
SETTING
Observational studies.
PARTICIPANTS
Cross-sectional samples with or without obesity, dysglycemia, and dyslipidemia, excluding prevalent cardiovascular disease and diabetes or dyslipidemia treatment. Age- and sex-matched by group.
INTERVENTIONS
None.
MAIN OUTCOME MEASURE(S): Gas chromatography-mass spectrometry detected 119 plasma metabolites. Cross-sectional associations with obesity, dyslipidemia, and dysglycemia were tested in discovery, with external replication of 37 metabolites. Single- and multi-metabolite markers were tested for association with longitudinal changes in risk factors.
RESULTS
Cross-sectional metabolite associations were identified with obesity (n = 26), dyslipidemia (n = 21), and dysglycemia (n = 11) in discovery. Glutamic acid, lactic acid, and sitosterol associated with all three risk factors in meta-analysis (P < 4.5 × 10−4). Metabolites associated with longitudinal risk factor changes were enriched for bioactive lipids. Multi-metabolite panels explained 2.5–15.3% of longitudinal changes in metabolic traits.
CONCLUSIONS
Cross-sectional results implicated dysregulated glutamate cycling and amino acid metabolism in metabolic risk. Certain bioactive lipids were associated with risk factors cross-sectionally and over time, suggesting their upstream role in risk factor progression. Functional studies are needed to validate findings and facilitate translation into treatments or preventive measures.
背景
代谢失调是肥胖、血脂异常和血糖异常等关键代谢危险因素的基础。
目的
通过横断面检测代谢物与危险因素的关联以及代谢物与危险因素随时间的变化，揭示代谢组学失调与代谢风险之间的机制联系。
设计
横断面研究——来自弗雷明汉心脏研究（FHS）的发现样本（n = 650；年龄36 - 69岁）和来自生物影像研究的复制样本（n = 670；年龄61 - 76岁），两者均采用析因设计，从体重指数、血脂和血糖的高分层与低分层中抽样。纵向研究——对554名FHS参与者进行5至7年的随访以观察危险因素的变化。
地点
观察性研究。
参与者
有或无肥胖、血糖异常和血脂异常的横断面样本，排除现患心血管疾病以及糖尿病或血脂异常治疗情况。按组进行年龄和性别匹配。
干预措施
无。
主要观察指标
气相色谱 - 质谱法检测119种血浆代谢物。在发现样本中检测代谢物与肥胖、血脂异常和血糖异常的横断面关联，并对37种代谢物进行外部复制验证。测试单代谢物和多代谢物标志物与危险因素纵向变化的关联。
结果
在发现样本中确定了代谢物与肥胖（n = 26）、血脂异常（n = 21）和血糖异常（n = 11）的横断面关联。在荟萃分析中，谷氨酸、乳酸和谷甾醇与所有三个危险因素相关（P < 4.5×10−4）。与危险因素纵向变化相关的代谢物富含生物活性脂质。多代谢物组合解释了代谢特征纵向变化的2.5% - 15.3%。
结论
横断面结果表明谷氨酸循环失调和氨基酸代谢与代谢风险有关。某些生物活性脂质在横断面和随时间均与危险因素相关，提示它们在危险因素进展中的上游作用。需要进行功能研究以验证研究结果，并促进将其转化为治疗或预防措施。
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