Metabolite Profiling Identifies Pathways Associated With Metabolic Risk in Humans

作者：Susan C. Cheng, Eugene P. Rhee, Martin G. Larson, Gregory D. Lewis, Elizabeth L. McCabe, Dongxiao Shen, Melinda J. Palma, Lee D. Roberts, André Dejam, Amanda L. Souza, Amy Deik, Martin Magnusson, Caroline S. Fox, Christopher J. O’Donnell, Ramachandran Srini Vasan, Olle Melander, Clary B. Clish, Robert Edgardo Gerszten, Thomas J. Wang · 发表于：Circulation · 年份：2012 · DOI：10.1161/circulationaha.111.067827 · 被引用次数：603 · 研究领域：Metabolomics and Mass Spectrometry Studies、Advanced Proteomics Techniques and Applications、Nutritional Studies and Diet

BACKGROUND: Although metabolic risk factors are known to cluster in individuals who are prone to developing diabetes mellitus and cardiovascular disease, the underlying biological mechanisms remain poorly understood. METHODS AND RESULTS: To identify pathways associated with cardiometabolic risk, we used liquid chromatography/mass spectrometry to determine the plasma concentrations of 45 distinct metabolites and to examine their relation to cardiometabolic risk in the Framingham Heart Study (FHS; n=1015) and the Malmö Diet and Cancer Study (MDC; n=746). We then interrogated significant findings in experimental models of cardiovascular and metabolic disease. We observed that metabolic risk factors (obesity, insulin resistance, high blood pressure, and dyslipidemia) were associated with multiple metabolites, including branched-chain amino acids, other hydrophobic amino acids, tryptophan breakdown products, and nucleotide metabolites. We observed strong associations of insulin resistance traits with glutamine (standardized regression coefficients, -0.04 to -0.22 per 1-SD change in log-glutamine; P<0.001), glutamate (0.05 to 0.14; P<0.001), and the glutamine-to-glutamate ratio (-0.05 to -0.20; P<0.001) in the discovery sample (FHS); similar associations were observed in the replication sample (MDC). High glutamine-to-glutamate ratio was associated with lower risk of incident diabetes mellitus in FHS (odds ratio, 0.79; adjusted P=0.03) but not in MDC. In experimental models, admini...