Circulation-cardiovascular Genetics 

About: Circulation-cardiovascular Genetics is an academic journal. The journal publishes majorly in the area(s): Population & Genome-wide association study. It has an ISSN identifier of 1942-3268. It is also open access. Over the lifetime, 982 publications have been published receiving 39237 citations.

Large-Scale Association Analysis Identifies 13 New Susceptibility Loci for Coronary Artery Disease

Abstract: 1. The CARDIoGRAM Consortium. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nature Genetics. 2011;43:333–338. ### Study Hypothesis Recently, genome-wide association studies (GWAS) have identified several common variants that are associated with risk of coronary artery disease (CAD) and myocardial infarction (MI). The authors state that the current loci discovered in CAD and MI GWAS explain only a small fraction of the heritability of this complex disease. The authors hypothesized that a larger study would provide more power to discover common variants with modest effect sizes. Therefore, they formed the Coronary ARtery DIsease Genome-wide Replication And Meta-analysis (CARDIoGRAM) consortium, which consisted of data from 14 GWAS of CAD and MI.1 ### How Was the Hypothesis Tested? The authors performed a meta-analysis of 14 GWAS of CAD comprising 22 233 cases and 64 762 control subjects, all of European ancestry. CAD was defined angiographically in a subset (n=7364) and by history in the entire sample. Presence of MI ranged from 48.1% to 100% of each cohort. After the meta-analysis, they genotyped the lead single-nucleotide polymorphisms (SNPs) within the most promising (defined a priori as P 90% power to detect effect sizes observed in the GWAS meta-analysis. Finally, to understand potential mechanisms and intermediate pathways by which novel loci may mediate risk, the authors interrogated 3 genome-wide studies that also assessed gene expression in multiple tissues, using human cell lines, a genome-wide map of allelic expression imbalance, and other human disease traits. ### Principal Findings The analysis of approximately 135 000 individuals more than doubled the number of loci with CAD association, yielding 13 previously unidentified loci and confirming at …

Circulating MicroRNA-208b and MicroRNA-499 Reflect Myocardial Damage in Cardiovascular Disease

Abstract: Background— Small RNA molecules, called microRNAs, freely circulate in human plasma and correlate with varying pathologies In this study, we explored their diagnostic potential in a selection of prevalent cardiovascular disorders Methods and Results— MicroRNAs were isolated from plasmas from well-characterized patients with varying degrees of cardiac damage: (1) acute myocardial infarction, (2) viral myocarditis, (3) diastolic dysfunction, and (4) acute heart failure Plasma levels of selected microRNAs, including heart-associated (miR-1, -133a, -208b, and -499), fibrosis-associated (miR-21 and miR-29b), and leukocyte-associated (miR-146, -155, and -223) candidates, were subsequently assessed using real-time polymerase chain reaction Strikingly, in plasma from acute myocardial infarction patients, cardiac myocyte–associated miR-208b and -499 were highly elevated, 1600-fold ( P <0005) and 100-fold ( P <00005), respectively, as compared with control subjects Receiver operating characteristic curve analysis revealed an area under the curve of 094 ( P <10−10) for miR-208b and 092 ( P <10−9) for miR-499 Both microRNAs correlated with plasma troponin T, indicating release of microRNAs from injured cardiomyocytes In viral myocarditis, we observed a milder but significant elevation of these microRNAs, 30-fold and 6-fold, respectively Plasma levels of leukocyte-expressed microRNAs were not significantly increased in acute myocardial infarction or viral myocarditis patients, despite elevated white blood cell counts In patients with acute heart failure, only miR-499 was significantly elevated (2-fold), whereas no significant changes in microRNAs studied could be observed in diastolic dysfunction Remarkably, plasma microRNA levels were not affected by a wide range of clinical confounders, including age, sex, body mass index, kidney function, systolic blood pressure, and white blood cell count Conclusions— Cardiac damage initiates the detectable release of cardiomyocyte-specific microRNAs-208b and -499 into the circulation

Epigenetic Signatures of Cigarette Smoking

Abstract: Background —DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders. Methods and Results —To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15,907 blood derived DNA samples from participants in 16 cohorts (including 2,433 current, 6,518 former, and 6,956 never smokers). Comparing current versus never smokers, 2,623 CpG sites (CpGs), annotated to 1,405 genes, were statistically significantly differentially methylated at Bonferroni threshold of p<1×10-7 (18,760 CpGs at False Discovery Rate (FDR)<0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant p<1×10-7 (2,623 CpGs at FDR<0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs. Conclusions —Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biologic effects of smoking, and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.

Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium: Design of prospective meta-analyses of genome-wide association studies from 5 cohorts.

Abstract: Background— The primary aim of genome-wide association studies is to identify novel genetic loci associated with interindividual variation in the levels of risk factors, the degree of subclinical disease, or the risk of clinical disease. The requirement for large sample sizes and the importance of replication have served as powerful incentives for scientific collaboration. Methods— The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium was formed to facilitate genome-wide association studies meta-analyses and replication opportunities among multiple large population-based cohort studies, which collect data in a standardized fashion and represent the preferred method for estimating disease incidence. The design of the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium includes 5 prospective cohort studies from the United States and Europe: the Age, Gene/Environment Susceptibility—Reykjavik Study, the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. With genome-wide data on a total of about 38 000 individuals, these cohort studies have a large number of health-related phenotypes measured in similar ways. For each harmonized trait, within-cohort genome-wide association study analyses are combined by meta-analysis. A prospective meta-analysis of data from all 5 cohorts, with a properly selected level of genome-wide statistical significance, is a powerful approach to finding genuine phenotypic associations with novel genetic loci. Conclusions— The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and collaborating non-member studies or consortia provide an excellent framework for the identification of the genetic determinants of risk factors, subclinical-disease measures, and clinical events. Received October 17, 2008; accepted December 17, 2008.

Quantitative Serum Nuclear Magnetic Resonance Metabolomics in Cardiovascular Epidemiology and Genetics

Abstract: Metabolomics is becoming common in epidemiology due to recent developments in quantitative profiling technologies and appealing results from their applications for understanding health and disease. Our team has developed an automated high-throughput serum NMR metabolomics platform that provides quantitative molecular data on 14 lipoprotein subclasses, their lipid concentrations and composition, apolipoprotein A-I and B, multiple cholesterol and triglyceride measures, albumin, various fatty acids as well as on numerous low-molecular-weight metabolites, including amino acids, glycolysis related measures and ketone bodies. The molar concentrations of these measures are obtained from a single serum sample with costs comparable to standard lipid measurements. We have analyzed almost 250 000 samples from around 100 epidemiological cohorts and biobanks and the new international set-up of multiple platforms will allow an annual throughput of more than 250 000 samples. The molecular data have been used to study type 1 and type 2 diabetes etiology as well as to characterize the molecular reflections of the metabolic syndrome, long-term physical activity, diet and lipoprotein metabolism. The results have revealed new biomarkers for early atherosclerosis, type 2 diabetes, diabetic nephropathy, cardiovascular disease and all-cause mortality. We have also combined genomics and metabolomics in diverse studies. We envision that quantitative high-throughput NMR metabolomics will be incorporated as a routine in large biobanks; this would make perfect sense both from the biological research and cost point of view - the standard output of over 200 molecular measures would vastly extend the relevance of the sample collections and make many separate clinical chemistry assays redundant.