Background-Molecular tools may provide insight into cardiovascular risk. We assessed whether metabolites discriminate coronary artery disease (CAD) and predict risk of cardiovascular events. Methods and Results-We performed mass-spectrometry-based profiling of 69 metabolites in subjects from the CATHGEN biorepository. To evaluate discriminative capabilities of metabolites for CAD, 2 groups were profiled: 174 CAD cases and 174 sex/race-matched controls ("initial"), and 140 CAD cases and 140 controls ("replication"). To evaluate the capability of metabolites to predict cardiovascular events, cases were combined ("event" group); of these, 74 experienced death/myocardial infarction during follow-up. A third independent group was profiled ("eventreplication" group; nϭ63 cases with cardiovascular events, 66 controls). Analysis included principal-components analysis, linear regression, and Cox proportional hazards. Two principal components analysis-derived factors were associated with CAD: 1 comprising branched-chain amino acid metabolites (factor 4, initial Pϭ0.002, replication Pϭ0.01), and 1 comprising urea cycle metabolites (factor 9, initial Pϭ0.0004, replication Pϭ0.01). In multivariable regression, these factors were independently associated with CAD in initial (factor 4, odds ratio [OR], 1.36; 95% CI, 1.06 to 1.74; Pϭ0.02; factor 9, OR, 0.67; 95% CI, 0.52 to 0.87; Pϭ0.003) and replication (factor 4, OR, 1.43; 95% CI, 1.07 to 1.91; Pϭ0.02; factor 9, OR, 0.66; 95% CI, 0.48 to 0.91; Pϭ0.01) groups. A factor composed of dicarboxylacylcarnitines predicted death/myocardial infarction (event group hazard ratio 2.17; 95% CI, 1.23 to 3.84; Pϭ0.007) and was associated with cardiovascular events in the event-replication group (OR, 1.52; 95% CI, 1.08 to 2.14; Pϭ0.01). Conclusions-Metabolite profiles are associated with CAD and subsequent cardiovascular events.(Circ Cardiovasc Genet. 2010;3:207-214.)Key Words: metabolism Ⅲ risk factors Ⅲ coronary artery disease C oronary artery disease (CAD) is the leading cause of death in industrialized countries. Many accepted risk factors for CAD are metabolic. However, there remains an incomplete mechanistic understanding of CAD risk and equally important, a need to refine our ability to identify individuals at highest risk of cardiovascular events. Given the complex nature of CAD, evaluation with more comprehensive tools may improve risk stratification and enhance our understanding of the disease process. Metabolomics, the study of small-molecule metabolites, may be particularly useful for the diagnosis of human disease. Studies have demonstrated heritability of metabolites in mice, 1 and we have shown that metabolite profiles are heritable in human families with early-onset CAD, 2 suggesting that the known heritability of CAD may be mediated at least in part through metabolic components measurable in peripheral blood. Clinical Perspective on p 214In this study, we performed quantitative profiling of 69 metabolites, including acylcarnitine species (byproducts of mitochondrial fatty aci...

Autistic disorder (AutD) is a complex genetic disease. Available evidence suggests that several genes contribute to the underlying genetic risk for the development of AutD. However, both etiologic heterogeneity and genetic heterogeneity confound the discovery of AutD-susceptibility genes. Chromosome 15q11-q13 has been identified as a strong candidate region on the basis of both the frequent occurrence of chromosomal abnormalities in that region and numerous suggestive linkage and association findings. Ordered-subset analysis (OSA) is a novel statistical method to identify a homogeneous subset of families that contribute to overall linkage at a given chromosomal location and thus to potentially help in the fine mapping and localization of the susceptibility gene within a chromosomal area. For the present analysis, a factor that represents insistence on sameness (IS)--derived from a principal-component factor analysis using data on 221 patients with AutD from the repetitive behaviors/stereotyped patterns domain in the Autism Diagnostic Interview-Revised--was used as a covariate in OSA. Analysis of families sharing high scores on the IS factor increased linkage evidence for the 15q11-q13 region, at the GABRB3 locus, from a LOD score of 1.45 to a LOD score of 4.71. These results narrow our region of interest on chromosome 15 to an area surrounding the gamma-aminobutyric acid-receptor subunit genes, in AutD, and support the hypothesis that the analysis of phenotypic homogeneous subtypes may be a powerful tool for the mapping of disease-susceptibility genes in complex traits.

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