Is proteomics of value in cardiovascular risk assessment?

Purpose of review To briefly summarize recently published evidence in the field of cardiovascular proteomics, focusing on its ability to improve cardiovascular risk stratification and critically discussing still open and burning issues and future perspectives of proteomics research. Recent findings Several epidemiological studies have demonstrated an improvement in cardiovascular risk prediction beyond traditional risk factors by adding novel biomarkers, identified by both discovery and targeted proteomics. However, only a moderate improvement in risk discrimination over clinical variables was observed. Moreover, despite different outcomes there was also a strong overlap of identified candi…

Differential Prognostic Value of Galectin-3 According to Carbohydrate Antigen 125 Levels in Transcatheter Aortic Valve Implantation

Galectin-3 (Gal-3) and carbohydrate antigen 125 (CA125) have been associated with adverse outcomes after transcatheter aortic valve implantation (TAVI). Experimental data have suggested a potential molecular interaction. Therefore, we assessed the association of Gal-3 and CA125 with prognosis after TAVI.A total of 439 patients were enrolled. The primary endpoint was a composite of all-cause mortality or readmission for worsening heart failure after TAVI.The primary endpoint occurred in 16.4%. Gal-3 was dichotomized at ≥ 8.71 ng/mL into elevated and not elevated. Gal-3 was elevated in 31.9% and was associated with a higher risk of the primary endpoint (25% vs 12.4%, HR, 2.26; P.001). After m…

Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium id…

Valor pronóstico diferencial de la galectina-3 según los valores de antígeno carbohidrato 125 para el implante percutáneo de válvula aórtica

Resumen Introduccion y objetivos La galectina-3 (Gal-3) y el antigeno carbohidrato 125 (CA125) han mostrado relacion con eventos adversos tras el implante percutaneo de valvula aortica (TAVI). Datos experimentales indican que podrian tener cierta interaccion molecular. El objetivo del presente estudio es establecer la asociacion de Gal-3 y CA125 con el pronostico tras el TAVI. Metodos Se incluyo en total a 439 pacientes. El objetivo primario fue el compuesto de mortalidad por todas las causas o reingreso por insuficiencia cardiaca tras el TAVI. Resultados El objetivo primario se produjo en el 16,4% de la muestra. Los valores de Gal-3 se dicotomizaron en elevados (≥ 8,71 ng/ml) y no elevados…

Large systems of path-repellent Brownian motions in a trap at positive temperature

We study a model of $ N $ mutually repellent Brownian motions under confinement to stay in some bounded region of space. Our model is defined in terms of a transformed path measure under a trap Hamiltonian, which prevents the motions from escaping to infinity, and a pair-interaction Hamiltonian, which imposes a repellency of the $N$ paths. In fact, this interaction is an $N$-dependent regularisation of the Brownian intersection local times, an object which is of independent interest in the theory of stochastic processes. The time horizon (interpreted as the inverse temperature) is kept fixed. We analyse the model for diverging number of Brownian motions in terms of a large deviation princip…

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions a…

P4500Prognostic value of galectin-3 according to carbohydrate antigen 125 in transcatheter aortic valve implantation

Duffy antigen receptor for chemokines (Darc) polymorphism regulates circulating concentrations of monocyte chemoattractant protein-1 and other inflammatory mediators

AbstractTo identify the genetic basis of circulating concentrations of monocyte chemoattractant protein-1 (MCP-1), we conducted genome-wide association analyses for MCP-1 in 3 independent cohorts (n = 9598). The strongest association was for serum MCP-1 with a nonsynonymous polymorphism, rs12075 (Asp42Gly) in DARC, the gene for Duffy antigen receptor for chemokines, a known vascular reservoir of proinflammatory cytokines (minor allele frequency, 45.6%; P < 1.0 * 10−323). This association was supported by family-based genetic linkage at a locus encompassing the DARC gene (genome-wide P = 8.0 * 10−13). Asp42Gly accounted for approximately 20% of the variability in serum MCP-1 concentration…

Determinants of elevated carbohydrate antigen 125 in patients with severe symptomatic aortic valve stenosis referred for transcatheter aortic valve implantation

Elevated carbohydrate antigen 125 (CA125) predicts adverse outcome after transcatheter aortic valve implantation (TAVI). While known underlying pathophysiological mechanisms of elevated CA125 include serosal effusions and inflammatory stimuli, clinical determinants associated with elevated CA125 in patients referred for TAVI remain unknown. Therefore, we investigated clinical, laboratory and echocardiographic determinants of elevated CA125 in patients with severe aortic valve stenosis referred for TAVI.This study includes 650 patients with severe aortic stenosis referred for TAVI. Baseline CA125 was determined by an immunoassay and dichotomized (elevated versus normal) based on the manufact…

Large-scale association analysis identifies new risk loci for coronary artery disease

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r 2 < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes …

A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including similar to 120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci ; of which, 18 …

Genome-wide Association Studies Identify Genetic Loci Associated with Albuminuria in Diabetes

Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10−10). Gene-by-diabetes interactions were…

Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders

International audience; C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 1…

Discovery and Fine Mapping of Serum Protein Loci through Transethnic Meta-analysis

Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p −8 ) for serum albumin ( HPN-SCN1B , GCKR-FNDC4 , SERPINF2-WDR81 , TNFRSF11A-ZCCHC2 , FRMD5-WDR76 , and RPS11-FCGRT , in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein ( TNFRS13B , 6q21.3, and ELL2 , in …

40(th) EASD Annual Meeting of the European Association for the Study of Diabetes : Munich, Germany, 5-9 September 2004

Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia

Increased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P = 4.89 &times; 10(-41)) and in 1690 AA subjects (rs505102; P = 1.05 &times; 10(-8)). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare M…

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation o…

New loci associated with kidney function and chronic kidney disease

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea 60 ml/min/1.73 m 2; n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P 5 × 10 8) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or…

Troponin I and cardiovascular risk prediction in the general population: the BiomarCaRE consortium

AIMS: Our aims were to evaluate the distribution of troponin I concentrations in population cohorts across Europe, to characterize the association with cardiovascular outcomes, to determine the predictive value beyond the variables used in the ESC SCORE, to test a potentially clinically relevant cut-off value, and to evaluate the improved eligibility for statin therapy based on elevated troponin I concentrations retrospectively.METHODS AND RESULTS: Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project, we analysed individual level data from 10 prospective population-based studies including 74 738 participants. We investigated the value of adding troponin …

Meta-Analysis of Genome-Wide Association Studies in &gt;80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels

Background— C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels. Methods and Results— We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in p…

Comparison of genetic risk prediction models to improve prediction of coronary heart disease in two large cohorts of the MONICA/KORA study

Abstract It is still unclear how genetic information, provided as single‐nucleotide polymorphisms (SNPs), can be most effectively integrated into risk prediction models for coronary heart disease (CHD) to add significant predictive value beyond clinical risk models. For the present study, a population‐based case‐cohort was used as a trainingset (451 incident cases, 1488 noncases) and an independent cohort as testset (160 incident cases, 2749 noncases). The following strategies to quantify genetic information were compared: A weighted genetic risk score including Metabochip SNPs associated with CHD in the literature (GRSMetabo); selection of the most predictive SNPs among these literature‐co…