Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Charles Perkins Centre and Heart Research Institute, The University of Sydney, Sydney, Australia.
J Clin Invest. 2017 Dec 1;127(12):4394-4402. doi: 10.1172/JCI95995. Epub 2017 Oct 30.
Unbiased, "nontargeted" metabolite profiling techniques hold considerable promise for biomarker and pathway discovery, in spite of the lack of successful applications to human disease. By integrating nontargeted metabolomics, genetics, and detailed human phenotyping, we identified dimethylguanidino valeric acid (DMGV) as an independent biomarker of CT-defined nonalcoholic fatty liver disease (NAFLD) in the offspring cohort of the Framingham Heart Study (FHS) participants. We verified the relationship between DMGV and early hepatic pathology. Specifically, plasma DMGV levels were correlated with biopsy-proven nonalcoholic steatohepatitis (NASH) in a hospital cohort of individuals undergoing gastric bypass surgery, and DMGV levels fell in parallel with improvements in post-procedure cardiometabolic parameters. Further, baseline DMGV levels independently predicted future diabetes up to 12 years before disease onset in 3 distinct human cohorts. Finally, we provide all metabolite peak data consisting of known and unidentified peaks, genetics, and key metabolic parameters as a publicly available resource for investigations in cardiometabolic diseases.
非靶向代谢组学分析技术在生物标志物和通路发现方面具有很大的应用潜力，尽管在人类疾病方面尚未成功应用。通过整合非靶向代谢组学、遗传学和详细的人类表型分析，我们在弗雷明汉心脏研究（Framingham Heart Study，FHS）参与者的后代队列中发现二甲胍戊酸（dimethylguanidino valeric acid，DMGV）是 CT 定义的非酒精性脂肪肝疾病（nonalcoholic fatty liver disease，NAFLD）的独立生物标志物。我们验证了 DMGV 与早期肝病理之间的关系。具体来说，在接受胃旁路手术的个体的医院队列中，血浆 DMGV 水平与经活检证实的非酒精性脂肪性肝炎（NASH）相关，并且 DMGV 水平随着术后心脏代谢参数的改善而平行下降。此外，在 3 个不同的人类队列中，基线 DMGV 水平独立预测了未来 12 年内糖尿病的发病，发病时间比疾病出现提前了 12 年。最后，我们提供了所有代谢物峰数据，包括已知和未识别的峰、遗传学和关键代谢参数，作为心脏代谢疾病研究的公开资源。
