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...

Objectives To develop RNA profiles that could serve as novel biomarkers for the response to aspirin. Background Aspirin reduces death and myocardial infarction (MI) suggesting that aspirin interacts with biological pathways that may underlie these events. Methods We administered aspirin, followed by whole blood RNA microarray profiling, in a discovery cohort of healthy volunteers (HV1,n=50), and two validation cohorts of volunteers (HV2,n=53) or outpatient cardiology patients (OPC, n=25). Platelet function was assessed by platelet function score (PFS; HV1/HV2) or VerifyNow Aspirin (OPC). Bayesian sparse factor analysis identified sets of coexpressed transcripts, which were examined for association with PFS in HV1 and validated in HV2 and OPC. Proteomic analysis confirmed the association of validated transcripts in platelet proteins. Validated gene sets were tested for association with death/MI in two patient cohorts (n=587, total) from RNA samples collected at cardiac catheterization. Results A set of 60 co-expressed genes named the “aspirin response signature” (ARS) was associated with PFS in HV1 (r = −0.31, p = 0.03), HV2 (r = −0.34, Bonferroni p = 0.03), and OPC (p = 0.046). Corresponding proteins for 17 ARS genes were identified in the platelet proteome, of which, six were associated with PFS. The ARS was associated with death/MI in both patient cohorts (odds ratio = 1.2, p = 0.01 and hazard ratio = 1.5, p = 0.001), independent of cardiovascular risk factors. Compared with traditional risk factors, reclassification (net reclassification index = 31 - 37%, p ≤ 0.0002) was improved by including the ARS or one of its genes, ITGA2B. Conclusions RNA profiles of platelet-specific genes are novel biomarkers for identifying those do not response adequately to aspirin and who are at risk for death/MI.

Genetic etiology of psychopathology symptoms and cognitive performance in schizophrenia is supported by candidate gene and polygenic risk score (PRS) association studies. Such associations are reported to be dependent on several factors - sample characteristics, illness phase, illness severity etc. We aimed to examine if schizophrenia PRS predicted psychopathology symptoms and cognitive performance in patients with chronic schizophrenia. We also examined if schizophrenia associated autosomal loci were associated with specific symptoms or cognitive domains.Case-only analysis using data from the Clinical Antipsychotics Trials of Intervention Effectiveness-Schizophrenia trials (n = 730). PRS was constructed using Psychiatric Genomics Consortium (PGC) leave one out genome wide association analysis as the discovery data set. For candidate region analysis, we selected 105-schizophrenia associated autosomal loci from the PGC study.We found a significant effect of PRS on positive symptoms at p-threshold (PT) of 0.5 (R2 = 0.007, p = 0.029, empirical p = 0.029) and negative symptoms at PT of 1e-07 (R2 = 0.005, p = 0.047, empirical p = 0.048). For models that additionally controlled for neurocognition, best fit PRS predicted positive (p-threshold 0.01, R2 = 0.007, p = 0.013, empirical p = 0.167) and negative symptoms (p-threshold 0.1, R2 = 0.012, p = 0.004, empirical p = 0.329). No associations were seen for overall neurocognitive and social cognitive performance tests. Post-hoc analyses revealed that PRS predicted working memory and vigilance performance but did not survive correction. No candidate regions that survived multiple testing corrections were associated with either symptoms or cognitive performance. Our findings point to potentially distinct pathogenic mechanisms for schizophrenia symptoms.

Objective To evaluate the extent of variability in functional responses among participants in the LIFE study, and to identify the relative contributions of intervention adherence, physical activity, and demographic and health characteristics to this variability. Design Secondary analysis of the Lifestyle Interventions and Independence for Elders (LIFE) study. Setting Multicenter U.S. institutions participating in the LIFE study. Participants A volunteer sample of 1635 sedentary men and women aged 70 to 89 years who were able to walk 400 m, but had physical limitations, defined as a score on the Short Physical Performance Battery (SPPB) of ≤9. Interventions Moderate-intensity physical activity (PA, n=818) consisting of aerobic, resistance and flexibility exercises performed both center-based (twice/wk) and in or around the home environment (3-4 times/wk) or health education (HE, n=817) consisting of weekly to monthly workshops covering relevant health information. Main Outcome Measures Physical function: gait speed over 400-m and lower extremity function (SPPB) assessed at baseline, six, twelve, and 24 months. Results Greater baseline physical function (gait speed and SPPB score) was inversely associated with Δ gait speed (regression coefficient β=−0.185, p<0.001) and ΔSPPB score (β=−0.365, p<0.001), while greater number of steps per day measured by accelerometry was positively associated with Δ gait speed (β=0.035, p<0.001) and Δ SPPB score (β=0.525, p<0.001). Other baseline factors associated with positive Δ gait speed and/or SPPB score include younger age (p<0.001), lower body mass index (p<0.001), and higher self-reported physical activity (p=0.002). Conclusions Several demographic and physical activity-related factors were associated with the extent of Δ functional outcomes among participants in the LIFE study. These factors should be considered when designing interventions for improving physical function among older adults with limited mobility.

Survivorship is a trait characterized by endurance and virility in the face of hardship. It is largely considered a psychosocial attribute developed during fatal conditions, rather than a biological trait for robustness in the context of complex, age-dependent diseases like coronary artery disease (CAD). The purpose of this paper is to present the novel phenotype, survivorship in CAD as an observed survival advantage concurrent with clinically significant CAD. We present a model for characterizing survivorship in CAD and its relationships with overlapping time- and clinically-related phenotypes. We offer an optimal measurement interval for investigating survivorship in CAD. We hypothesize genetic contributions to this construct and review the literature for evidence of genetic contribution to overlapping phenotypes in support of our hypothesis. We also present preliminary evidence of genetic effects on survival in people with clinically significant CAD from a primary case-control study of symptomatic coronary disease. Identifying gene variants that confer improved survival in the context of clinically appreciable CAD may improve our understanding of cardioprotective mechanisms acting at the gene level and potentially impact patients clinically in the future. Further, characterizing other survival-variant genetic effects may improve signal-to-noise ratio in detecting gene associations for CAD.