Statistical colocalization of monocyte gene expression and genetic risk variants for type 1 diabetes

One mechanism by which disease-associated DNA variation can alter disease risk is altering gene expression. However, linkage disequilibrium (LD) between variants, mostly single-nucleotide polymorphisms (SNPs), means it is not sufficient to show that a particular variant associates with both disease and expression, as there could be two distinct causal variants in LD. Here, we describe a formal statistical test of colocalization and apply it to type 1 diabetes (T1D)-associated regions identified mostly through genome-wide association studies and expression quantitative trait loci (eQTLs) discovered in a recently determined large monocyte expression data set from the Gutenberg Health Study (1…

New susceptibility locus for coronary artery disease on chromosome 3q22.3

We present a three-stage analysis of genome-wide SNP data in 1,222 German individuals with myocardial infarction and 1,298 controls, in silico replication in three additional genome-wide datasets of coronary artery disease (CAD) and subsequent replication in approximately 25,000 subjects. We identified one new CAD risk locus on 3q22.3 in MRAS (P = 7.44 x 10(-13); OR = 1.15, 95% CI = 1.11-1.19), and suggestive association with a locus on 12q24.31 near HNF1A-C12orf43 (P = 4.81 x 10(-7); OR = 1.08, 95% CI = 1.05-1.11).

B-Type Natriuretic Peptide and the Risk of Cardiovascular Events and Death in Patients With Stable Angina Results From the AtheroGeneStudy

ObjectivesThe aim of this study was to assess the predictive value of the cardiac hormone B-type natriuretic peptide (BNP) for long-term outcome in a large cohort of stable angina patients.BackgroundRecent data suggest a role of BNP in stable ischemic heart disease beyond its known value in heart failure and acute coronary syndromes.MethodsIn 1,085 patients with coronary artery disease (CAD) baseline levels of BNP were prospectively associated with cardiovascular (CV) events during a mean follow-up of 2.5 years.ResultsBNP concentrations were significantly elevated in patients with future CV events (median [25th/75th interquartile range] 119.2 [43.6/300.4] pg/ml vs. 36.2 [11.3/94.6] pg/ml; p…

Removing Batch Effects from Longitudinal Gene Expression - Quantile Normalization Plus ComBat as Best Approach for Microarray Transcriptome Data

International audience; Technical variation plays an important role in microarray-based gene expression studies, and batch effects explain a large proportion of this noise. It is therefore mandatory to eliminate technical variation while maintaining biological variability. Several strategies have been proposed for the removal of batch effects, although they have not been evaluated in large-scale longitudinal gene expression data. In this study, we aimed at identifying a suitable method for batch effect removal in a large study of microarray-based longitudinal gene expression. Monocytic gene expression was measured in 1092 participants of the Gutenberg Health Study at baseline and 5-year fol…

C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S-independent mechanism: results from genome-wide association and gene expression analyses followed by case-control studies

3 Figures. 2 Tables. The online version of this article contains a data supplement.

Genome-Wide Haplotype Analysis of Cis Expression Quantitative Trait Loci in Monocytes

In order to assess whether gene expression variability could be influenced by several SNPs acting in cis, either through additive or more complex haplotype effects, a systematic genome-wide search for cis haplotype expression quantitative trait loci (eQTL) was conducted in a sample of 758 individuals, part of the Cardiogenics Transcriptomic Study, for which genome-wide monocyte expression and GWAS data were available. 19,805 RNA probes were assessed for cis haplotypic regulation through investigation of ∼2,1×109 haplotypic combinations. 2,650 probes demonstrated haplotypic p-values >104-fold smaller than the best single SNP p-value. Replication of significant haplotype effects were tested f…

A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk

Combined analyses of gene networks and DNA sequence variation can provide new insights into the aetiology of common diseases that may not be apparent from genome-wide association studies alone. Recent advances in rat genomics are facilitating systems-genetics approaches. Here we report the use of integrated genome-wide approaches across seven rat tissues to identify gene networks and the loci underlying their regulation. We defined an interferon regulatory factor 7 (IRF7)-driven inflammatory network (IDIN) enriched for viral response genes, which represents a molecular biomarker for macrophages and which was regulated in multiple tissues by a locus on rat chromosome 15q25. We show that Epst…

Resistin, acute coronary syndrome and prognosis results from the AtheroGene study

Resistin, an adipocyte and macrophage derived cytokine, causes insulin resistance and glucose intolerance. We investigated the impact of resistin as a diagnostic marker in patients with acute coronary syndrome and its prognostic value for future cardiovascular events.Resistin levels were determined in 1153 patients with stable angina (SAP), 380 patients with unstable angina, 278 patients with non-ST-elevation myocardial infarction (NSTEMI) and 111 patients with ST-elevation myocardial infarction (STEMI). All patients have been followed up for a median follow-up of 2.6 years. During follow-up, 70 patients died from cardiovascular causes.Compared to SAP, resistin levels (5.1 ng/mL in SAP) wer…

The Choice of the Filtering Method in Microarrays Affects the Inference Regarding Dosage Compensation of the Active X-Chromosome

BackgroundThe hypothesis of dosage compensation of genes of the X chromosome, supported by previous microarray studies, was recently challenged by RNA-sequencing data. It was suggested that microarray studies were biased toward an over-estimation of X-linked expression levels as a consequence of the filtering of genes below the detection threshold of microarrays.Methodology/principal findingsTo investigate this hypothesis, we used microarray expression data from circulating monocytes in 1,467 individuals. In total, 25,349 and 1,156 probes were unambiguously assigned to autosomes and the X chromosome, respectively. Globally, there was a clear shift of X-linked expressions toward lower levels…

Cystatin C and cardiovascular mortality in patients with coronary artery disease and normal or mildly reduced kidney function: results from the AtheroGene study

Aims Chronic kidney disease is associated with increased risk of cardiovascular disease. Cystatin C is a promising marker to reliably mirror renal function. The role of cystatin C in patients with coronary artery disease (CAD) and normal or mildly reduced kidney function is the subject of current investigation. Methods and results In 2162 patients, over the whole spectrum of CAD, baseline cystatin C concentrations were measured. Patients with an estimated glomerular filtration rate of ≤60 mL/min per 1.73 m2 ( n = 295) were excluded. In patients with complete follow-up information ( n = 1827), 66 cardiovascular deaths were registered during a median follow-up of 3.65 years. Logarithmically t…

Prognostic value of plasma tissue factor and tissue factor pathway inhibitor for cardiovascular death in patients with coronary artery disease: the AtheroGene study.

Summary. Background: Tissue factor (TF) and its specific inhibitor, tissue factor pathway inhibitor (TFPI), are important contributors to the initiation of the coagulation process. Objectives: To compare plasma levels of soluble TF (sTF) and free-TFPI (f-TFPI) between patients with stable angina pectoris (SAP) and acute coronary syndrome (ACS) and to assess the impact of the two variables on long-term prognosis. Patients/methods: Patients with SAPs (n = 1146) and acute coronary syndrome (n = 523) from the AtheroGene study were included and followed for 2.3 years. Because of the strong impact of unfractionated heparin (UFH) on f-TFPI levels, but not on sTF levels, patients having received UF…

Activated thrombin activatable fibrinolysis inhibitor levels are associated with the risk of cardiovascular death in patients with coronary artery disease: the AtheroGene study

Summary. Background: Thrombin activatable fibrinolysis inhibitor (TAFI) attenuates fibrinolysis. Results on the association between TAFI levels and the risk of coronary artery disease (CAD) are inconsistent. Objectives: We investigated the association between TAFI levels and the risk of cardiovascular events in CAD. Patients/Methods: 1668 individuals with angiographically proven CAD at baseline were followed for a median of 2.3 years, as part of the prospective AtheroGene cohort. Fifty-six deaths from cardiovascular (CV) causes and 35 non-fatal CV events were observed. Results: At baseline, three TAFI measurements were available: one evaluating the total amount of TAFI (t-TAFI), one measuri…

Comprehensive exploration of the effects of miRNA SNPs on monocyte gene expression.

We aimed to assess whether pri-miRNA SNPs (miSNPs) could influence monocyte gene expression, either through marginal association or by interacting with polymorphisms located in 3'UTR regions (3utrSNPs). We then conducted a genome-wide search for marginal miSNPs effects and pairwise miSNPs × 3utrSNPs interactions in a sample of 1,467 individuals for which genome-wide monocyte expression and genotype data were available. Statistical associations that survived multiple testing correction were tested for replication in an independent sample of 758 individuals with both monocyte gene expression and genotype data. In both studies, the hsa-mir-1279 rs1463335 was found to modulate in cis the expres…

Comparative impact of multiple biomarkers and N-terminal pro-brain natriuretic peptide in the context of conventional risk factors for the prediction of recurrent cardiovascular events in the heart outcomes prevention evaluation (HOPE) Study

Background— Individual markers of inflammation may add incremental predictive value in the context of conventionally available risk factors. We evaluated the ability of 9 inflammatory biomarkers, microalbuminuria, and N-terminal pro-brain natriuretic peptide (Nt-proBNP) to improve cardiovascular risk prediction beyond that obtained from traditional risk factors in a secondary-prevention population. Methods and Results— We measured biomarkers representing the acute-phase reaction (C-reactive protein, fibrinogen, and interleukin-6), proinflammatory pathways (soluble tumor necrosis factor receptor-1 and -2, soluble interleukin-1 receptor antagonist, and interleukin-18), endothelial activation…

A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a major cause of heart failure with a high familial recurrence risk. So far, the genetics of DCM remains largely unresolved. We conducted the first genome-wide association study (GWAS) to identify loci contributing to sporadic DCM.One thousand one hundred and seventy-nine DCM patients and 1108 controls contributed to the discovery phase. Pools of DNA stratified on disease status, population, age, and gender were constituted and used for testing association of DCM with 517 382 single nucleotide polymorphisms (SNPs). Three DCM-associated SNPs were confirmed by individual genotyping (P5.0 10(-7)), and two of them, rs10927875 and rs2234962, were replicated in ind…

Interleukin-18 Is a Strong Predictor of Cardiovascular Death in Stable and Unstable Angina

Background — Interleukin (IL)-18 plays a central role in orchestrating the cytokine cascade and accelerates atherosclerosis and plaque vulnerability in animal models. However, epidemiological data evaluating the role of IL-18 levels in atherosclerosis are lacking. Methods and Results — In a prospective study of 1229 patients with documented coronary artery disease, we measured baseline serum concentrations of IL-18 and other markers of inflammation. During the follow-up period (median, 3.9 years), 95 patients died of cardiovascular causes. Median serum concentrations of IL-18 were significantly higher among patients who had a fatal cardiovascular event than among those who did not (68.4 ve…

A follow-up study of a genome-wide association scan identifies a susceptibility locus for venous thrombosis on chromosome 6p24.1.

International audience; To identify genetic susceptibility factors conferring increased risk of venous thrombosis (VT), we conducted a multistage study, following results of a previously published GWAS that failed to detect loci for developing VT. Using a collection of 5862 cases with VT and 7112 healthy controls, we identified the HIVEP1 locus on chromosome 6p24.1 as a susceptibility locus for VT. Indeed, the HIVEP1 rs169713C allele was associated with an increased risk for VT, with an odds ratio of 1.20 (95% confidence interval 1.13-1.27, p = 2.86 x 10(-9)). HIVEP1 codes for a protein that participates in the transcriptional regulation of inflammatory target genes by binding specific DNA …

SELPLG Gene Polymorphisms in Relation to Plasma SELPLG Levels and Coronary Artery Disease

P-selectin and P-selectin glycoprotein ligand (SELPLG, selectin P ligand) constitute a receptor/ligand complex that is likely to be involved in the development of atherosclerosis and its complications. While the genetic variability of P-selectin has already been investigated in depth, that of the SELPLG gene has not yet been extensively explored. The coding and regulatory sequences of the SELPLG were screened and nine polymorphisms were identified. The identified polymorphisms were genotyped in the AtheroGene study, a case-control study of coronary artery disease (CAD). Haplotype analysis revealed that two polymorphisms of SELPLG, the M62I and the VNTR, independently influenced plasma SELPL…

Glutathione Peroxidase 1 Activity and Cardiovascular Events in Patients With Coronary Artery Disease

Along with superoxide dismutase, glutathione peroxidase 1 is one of the cellular antioxidant enzymes that have a key role in controlling reactive oxygen species. It uses glutathione to reduce hydrogen peroxide to water and lipid peroxides to their respective alcohols. There are suggestions from in vitro and animal studies that these enzymes could protect against atherosclerosis. This prospective study examined the possibility that relatively high activity of antioxidant enzymes protects against cardiovascular events. The study population included 636 patients suspected of having coronary artery disease who were followed for a median period of 4.7 years. Stable angina was present in 510 pati…

Circulating Cell Adhesion Molecules and Death in Patients With Coronary Artery Disease

Background —Vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, and E-selectin mediate adhesion and transmigration of leukocytes to the vascular endothelial wall and may promote plaque growth and instability. In a prospective study, we evaluated the effect of soluble adhesion molecules on the risk of future cardiovascular events among patients with angiographically documented coronary artery disease (CAD). Methods and Results —We obtained baseline samples from a prospective cohort of 1246 patients with CAD. Besides various markers of inflammation, soluble VCAM-1 (sVCAM-1), sICAM-1, and sE-selectin were determined. Follow-up information on cardiovascular even…

A029 Identification of polymorphisms in the gene encoding secreted phospholipase A2 group X and study of their role in coronary artery disease. The atherogene study

Human secreted phospholipases A2 (sPLA2s) represent novel attractive therapeutic targets and biomarkers in coronary artery diseases (CAD). We have shown that human Group X sPLA2 (hGX sPLA2) is present in atherosclerotic lesions and that hGX sPLA2 modified LDL induces foam cell formation. To elucidate whether hGX sPLA2 has a causative role in CAD we have screened the human PLA2G10 gene to identify frequent polymorphisms, and we have examined their possible association with cardiovascular end-points and intermediate inflammatory phenotypes in a large prospective study of patients with CAD (the AtheroGene study). Although no significant association was found between the various polymorphisms i…

Copeptin Improves Early Diagnosis of Acute Myocardial Infarction

ObjectivesEarly identification of myocardial infarction in chest pain patients is crucial to identify patients at risk and to maintain a fast treatment initiation.BackgroundThe aim of the current investigation is to test whether determination of copeptin, an indirect marker for arginin-vasopressin, adds diagnostic information to cardiac troponin in early evaluation of patients with suspected myocardial infarction.MethodsBetween January 2007 and July 2008, patients with suspected acute coronary syndrome were consecutively enrolled in this multicenter study. Copeptin, troponin T (TnT), myoglobin, and creatine kinase-myocardial band were determined at admission and after 3 and 6 h.ResultsOf 1,…

Sensitive Troponin I Assay in Early Diagnosis of Acute Myocardial Infarction

BACKGROUND Cardiac troponin testing is central to the diagnosis of acute myocardial infarction. We evaluated a sensitive troponin I assay for the early diagnosis and risk stratification of myocardial infarction. METHODS In a multicenter study, we determined levels of troponin I as assessed by a sensitive assay, troponin T, and traditional myocardial necrosis markers in 1818 consecutive patients with suspected acute myocardial infarction, on admission and 3 hours and 6 hours after admission. RESULTS For samples obtained on admission, the diagnostic accuracy was highest with the sensitive troponin I assay (area under the receiver-operating-characteristic curve [AUC], 0.96), as compared with t…

Plasma PAF-acetylhydrolase in patients with coronary artery disease: results of a cross-sectional analysis.

Inflammation underlies both onset and perpetuation of atherosclerosis. Plasma lipoproteins transport the platelet-activating factor-acetylhydrolase (PAF-AH) with potentially anti-inflammatory activities. Our aim was to determine whether PAF-AH activity was associated with inflammatory markers and with coronary artery disease (CAD). PAF-AH activity and a panel of inflammatory mediators were measured in plasma of 496 patients with CAD and in 477 controls; 276 patients presented with stable angina pectoris and 220 with acute coronary syndrome (ACS). Individuals within the highest quartile of PAF-AH activity had an 1.8-fold increase in CAD risk [95% confidence interval (CI), 1.01 to 3.2; P = 0.…

Midregional Proadrenomedullin for Prediction of Cardiovascular Events in Coronary Artery Disease: Results from the AtheroGene Study

Abstract BACKGROUND Midregional proadrenomedullin (MR-proADM) is a newly identified prognostic marker in heart failure. We evaluated the prognostic impact of MR-proADM in a cohort of patients with symptomatic coronary artery disease according to their clinical presentation. METHODS We measured baseline MR-proADM concentrations in 2240 individuals from the prospective AtheroGene study and evaluated the prognostic impact on future fatal and nonfatal cardiovascular events during a follow-up period of 3.6 (1.6) years. RESULTS The sample comprised 1355 individuals with stable angina pectoris (SAP) and 885 with acute coronary syndrome (ACS). A cardiovascular event occurred in 192 people. Individu…

Prognostic value of tissue inhibitor of metalloproteinase-1 for cardiovascular death among patients with cardiovascular disease: results from the AtheroGene study.

Aims Metalloproteinases are proteolytic enzymes, which decompose the extracellular matrix, influence cardiac remodelling, and are inhibited by tissue inhibitor of metalloproteinases (TIMPs). Little is known about the prognostic impact of the TIMP-1/matrix metalloproteinase complex in patients with future cardiovascular death. Methods and results In 1979 patients with suspected coronary artery disease (CAD), TIMP-1 has been determined at baseline. Among 1945 (98.4%) patients with a mean follow-up period of 2.6±1.2 years, 75 patients died because of cardiovascular causes. Mean concentrations of TIMP-1 were higher among patients who experienced a fatal cardiovascular event than among those who…

Influence of sex and genetic variability on expression of X-linked genes in human monocytes

Abstract In humans, the fraction of X-linked genes with higher expression in females has been estimated to be 5% from microarray studies, a proportion lower than the 25% of genes thought to escape X inactivation. We analyzed 715 X-linked transcripts in circulating monocytes from 1,467 subjects and found an excess of female-biased transcripts on the X compared to autosomes (9.4% vs 5.5%, p  −5 ). Among the genes not previously known to escape inactivation, the most significant one was EFHC2 whose 20% of variability was explained by sex. We also investigated cis expression quantitative trait loci (eQTLs) by analyzing 15,703 X-linked SNPs. The frequency and magnitude of X-linked cis eQTLs were…

Multiple marker approach to risk stratification in patients with stable coronary artery disease

Aims Multimarker approaches for risk prediction in coronary artery disease have remained inconsistent. We assessed multiple biomarkers representing distinct pathophysiological pathways in relation to cardiovascular events in stable angina. Methods and results We investigated 12 biomarkers reflecting inflammation [C-reactive protein, growth-differentiation factor (GDF)-15, neopterin], lipid metabolism (apolipoproteins AI, B100), renal function (cystatin C, serum creatinine), and cardiovascular function and remodelling [copeptin, C-terminal-pro-endothelin-1, mid-regional-pro-adrenomedullin (MR-proADM), mid-regional-pro-atrial natriuretic peptide (MR-proANP), N-terminal-pro-B-type natriuretic …

Glutathione Peroxidase-1 and Homocysteine for Cardiovascular Risk Prediction

Objectives This prospective study was designed to evaluate the effect of joint determination of two important contrary biomarkers—homocysteine and glutathione peroxidase (GPx)-1—on cardiovascular risk stratification. Background Homocysteine plasma levels have been associated with cardiovascular risk. Experimental data suggest that antioxidative GPx-1 activity modulates cardiovascular risk associated with homocysteine. Methods In 643 patients with coronary artery disease, we performed a prospective study to assess the risk of homocysteine plasma levels and GPx-1 activity on long-term cardiovascular risk with a median follow-up of 7.1 years. Results Both homocysteine and GPx-1 were among the …

Genetics and Beyond – The Transcriptome of Human Monocytes and Disease Susceptibility

BACKGROUND: Variability of gene expression in human may link gene sequence variability and phenotypes; however, non-genetic variations, alone or in combination with genetics, may also influence expression traits and have a critical role in physiological and disease processes. METHODOLOGY/PRINCIPAL FINDINGS: To get better insight into the overall variability of gene expression, we assessed the transcriptome of circulating monocytes, a key cell involved in immunity-related diseases and atherosclerosis, in 1,490 unrelated individuals and investigated its association with >675,000 SNPs and 10 common cardiovascular risk factors. Out of 12,808 expressed genes, 2,745 expression quantitative trait …

Differential haplotypic expression of the interleukin-18 gene

Interleukin 18 (IL-18) is suspected to play an important role in atherosclerosis and plaque vulnerability. We had previously shown that haplotypes combining two IL18 gene polymorphisms in complete linkage disequilibrium, C-105T (rs360717) in 5'-untranslated region (UTR) and A+183G (rs5744292) in 3'-UTR, were related to IL-18 circulating levels and cardiovascular outcome, the C(-105) G(+183) haplotype being associated with lower IL-18 levels and lower cardiovascular risk. This study was aimed at investigating the functional role of the two polymorphisms and their haplotypes on IL18 expression levels. Allelic imbalance experiments conducted in 24 and 20 subjects heterozygous for the C-105T an…

Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease.

Background—Matrix metalloproteinase (MMP)-9 secretion by macrophages and other inflammatory cells accelerates atherosclerotic progression and destabilizes vulnerable plaque in animal models. However, epidemiological data evaluating the prognostic impact of circulating concentrations and functional genetic variations of MMP-9 are lacking.Methods and Results—In a prospective study of 1127 patients with documented coronary artery disease, we measured baseline plasma MMP-9 levels and determined the MMP-9/C-1562T and MMP-9/R279Q genotypes. During the follow-up period (mean of 4.1 years), 97 patients died from cardiovascular (CV) causes. Median concentrations of MMP-9 were significantly higher am…

Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans.

One major expectation from the transcriptome in humans is to characterize the biological basis of associations identified by genome-wide association studies. So far, few cis expression quantitative trait loci (eQTLs) have been reliably related to disease susceptibility. Trans-regulating mechanisms may play a more prominent role in disease susceptibility. We analyzed 12,808 genes detected in at least 5% of circulating monocyte samples from a population-based sample of 1,490 European unrelated subjects. We applied a method of extraction of expression patterns—independent component analysis—to identify sets of co-regulated genes. These patterns were then related to 675,350 SNPs to identify maj…

B-Type Natriuretic Peptide and the Risk of Cardiovascular Events and Death in Patients With Stable Angina

B-Type Natriuretic Peptide and the Risk of Cardiovascular Events and Death in Patients With Stable Angina: Results From the AtheroGeneStudyRenate Schnabel, Edith Lubos, Hans J. Rupprecht, Christine...

Analysis of N-terminal-pro-brain natriuretic peptide and C-reactive protein for risk stratification in stable and unstable coronary artery disease: results from the AtheroGene study

Aims N-terminal-pro-brain natriuretic peptide (Nt-proBNP) is a reliable risk predictor in acute coronary artery disease (CAD). Little is known about patients with stable angina pectoris (SAP). We aimed to investigate the prognostic impact of Nt-proBNP in a population with CAD especially focussing on patients with SAP. Methods and results We obtained baseline samples from a prospective cohort of 904 consecutive patients with CAD. Cardiovascular events were registered during followup (median 2 years; maximum 3.7 years). Baseline Nt-proBNP was significantly higher among individuals with cardiovascular events compared with those without (711.5 vs. 238.8 pg/mL; P , 0.0001). A similar association…

Common genetic variation of the cholesteryl ester transfer protein gene strongly predicts future cardiovascular death in patients with coronary artery disease

OBJECTIVES We sought to evaluate the association between cholesteryl ester transfer protein (CETP) genotypes and the risk of future cardiovascular mortality in patients with coronary artery disease (CAD). BACKGROUND Polymorphisms of the CETP gene influence CETP activity and high-density lipoprotein (HDL) cholesterol concentration and might affect the long-term prognosis and response to statin therapy in patients with CAD. METHODS We used serum samples and deoxyribonucleic acid collected at baseline from a prospective cohort of 1,211 patients with CAD prospectively followed up (median follow-up of 4.1 years), 82 of whom experienced a fatal cardiovascular event. The CETP/C-629A and I405V poly…

The value of N-terminal fragment of brain natriuretic peptide and tissue inhibitor of metalloproteinase-1 levels as predictors of cardiovascular outcome in the LIPID study

Aims We sought to determine the association between two major biomarkers, the inactive N-terminal fragment of brain natriuretic peptide (NT-proBNP) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and long-term cardiovascular outcomes in a cohort of subjects who had a myocardial infarction or unstable angina 3–36 months previously. Methods and results Plasma NT-proBNP and TIMP-1 were measured in a nested case control study of 250 randomly matched subject pairs enrolled in the long-term intervention with pravastatin in ischaemic disease (LIPID) and LIPID extended follow-up studies. Cases ( n = 250) were defined as those who had a cardiovascular death, non-fatal myocardial infarction or s…

Impact of C-reactive protein and fibrinogen on cardiovascular prognosis in patients with stable angina pectoris: the AtheroGene study.

Aims C-reactive protein and fibrinogen have been extensively studied and shown to be predictive for a first cardiovascular event in healthy individuals. We evaluated the potential clinical use of C-reactive protein and fibrinogen in patients already suffering from coronary artery disease (CAD). Methods and results In a substudy of the prospective Athero Gene registry, we assessed in 1806 patients with documented CAD and stable angina pectoris, the risk of cardiovascular death and non-fatal myocardial infarction ( n =183) over a median follow-up of 3.5 (maximum 7.7) years according to baseline levels of C-reactive protein and fibrinogen. C-reactive protein and fibrinogen were associated with…

Impact of pathogen burden in patients with coronary artery disease in relation to systemic inflammation and variation in genes encoding cytokines.

The number of infectious pathogens to which an individual has been exposed (pathogen burden) has been linked to the development and the prognosis of coronary artery disease (CAD). The interaction among infection, genetic host susceptibility, and CAD remains unclear. This study was aimed at evaluating the modulation of the association between CAD and pathogen burden, by serum levels of inflammatory markers and polymorphisms of the interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha genes. Immmunoglobulin (Ig) G or IgA antibodies to 8 pathogens were determined in 991 patients with CAD and 333 control subjects. Serum levels of high-sensitivity C-reactive protein, fibrinogen, IL-6, and TNF…

Homozystein, Methylentetrahydrofolatreduktase/C677T-Genotyp und Risiko für koronare Herzkrankheit

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…

Einfluss genetischer Variationen des Cholesterylestertransferproteingens auf die Pr�valenz der koronaren Herzerkrankung

Mehrere funktionelle Polymorphismen des Cholesterylestertransferprotein( CETP)-Gens beeinflussen die CETP-Aktivitat und die High-density-lipoprotein(HDL)-Cholesterin-Konzentration. Neben anderen funktionellen Varianten wird vornehmlich der Promotorpolymorphismus CETP/C-629A als Risikofaktor der koronaren Herzerkrankung (KHK) diskutiert. Wir untersuchten in einer grosen Fall-/Kontroll-Studie den Einfluss verschiedener CETP-Genotypen und Haplotypen auf die HDL-Konzentration sowie die Pravalenz der KHK. Bei 1214 Patienten mit dokumentierter KHK sowie 574 Populationskontrollen wurden neben den klassischen Risikofaktoren folgende CETP-Polymorphismen bestimmt: C-629A, TaqIB, I405V, R451Q und A373…

Adrenomedullin and arterial stiffness: integrative approach combining monocyte ADM expression, plasma MR-Pro-ADM, and genome-wide association study.

Background— Adrenomedullin (ADM) is a circulating vasoactive peptide involved in vascular homeostasis and endothelial function. Single nucleotide polymorphisms of the ADM gene are associated with blood pressure variability, and elevated levels of plasma midregional proadrenomedullin (MR-pro-ADM) are associated with cardiovascular diseases. Methods and Results— We investigated the sources of variability of ADM gene expression and plasma MR-pro-ADM concentrations in the general population, and their relationship with markers of atherosclerosis. MR-pro-ADM levels were assessed in 4155 individuals who underwent evaluation of carotid intima-media thickness and arterial rigidity (reflection inde…

Asymmetric Dimethylarginine and the Risk of Cardiovascular Events and Death in Patients With Coronary Artery Disease

As a competitive inhibitor of endothelial nitric oxide synthase, asymmetric dimethylarginine (ADMA) has been related to atherosclerotic disease. Little is known about the prognostic impact of baseline ADMA determination. In a prospective cohort of 1908 patients with coronary artery disease, we assessed baseline serum concentration of ADMA in 1874 consecutive patients with coronary artery disease. One hundred fourteen individuals developed the primary end point of death from cardiovascular causes or nonfatal myocardial infarction during a mean follow-up of 2.6±1.2 years. Median concentrations of ADMA levels were higher among individuals who subsequently developed the primary end point than …

A multiple biomarker risk score for guiding clinical decisions using a decision curve approach.

Aims: We assessed whether a cardiovascular risk model based on classic risk factors (e.g. cholesterol, blood pressure) could refine disease prediction if it included novel biomarkers (C-reactive protein, N-terminal pro-B-type natriuretic peptide, troponin I) using a decision curve approach which can incorporate clinical consequences. Methods and results: We evaluated whether a model including biomarkers and classic risk factors could improve prediction of 10 year risk of cardiovascular disease (CVD; chronic heart disease and ischaemic stroke) against a classic risk factor model using a decision curve approach in two prospective MORGAM cohorts. This included 7739 men and women with 457 CVD …