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).

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…

KCND3 is a novel susceptibility locus for early repolarization

AbstractThe presence of an early repolarization pattern (ERP) on the surface electrocardiogram (ECG) is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait but molecular genetic determinants are unknown. We assessed the ERP in 12-lead ECGs of 39,456 individuals and conducted a two-stage meta-analysis of genome-wide association studies (GWAS). In the discovery phase, we included 2,181 cases and 23,641 controls from eight European ancestry studies and identified 19 genome-wide significant (p<5E-8) variants in the KCND3 (potassium voltage gated channel subfamily D member 3) gene with a p-value of 4.6E-10. …

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…

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…

Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)

PubMed: 30270054

Pooling and expanding registries of familial hypercholesterolaemia to assess gaps in care and improve disease management and outcomes: Rationale and design of the global EAS Familial Hypercholesterolaemia Studies Collaboration

WOS: 000393031600001

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

Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach

Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17 000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Ill…

Improvement in Risk Stratification in Transcatheter Aortic Valve Implantation Using a Combination of the Tumor Marker CA125 and the Logistic EuroSCORE

Conventional risk scores have not been accurate in predicting peri- and postprocedural risk of patients undergoing transcatheter aortic valve implantation (TAVI). Elevated levels of the tumor marker carbohydrate antigen 125 (CA125) have been linked to adverse outcomes after TAVI. We studied the additional value of CA125 to that of the EuroSCORE in predicting long-term mortality after TAVI.During a median follow-up of 59 weeks, 115 of 422 patients (27%) died after TAVI. Mortality was higher with elevated CA125 (30 U/mL) and EuroSCORE (median) (47% vs 20%, P.001 and 38% vs 16%, P.001, respectively). In the multivariable analysis, CA125 (30 U/mL) remained an independent predictor of mortality …

Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data.

Context Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. Objective To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. Design, Setting, and Participants Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nuc…

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…

Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)

Background The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally. Methods Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Dat…

KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern

BACKGROUND: The presence of an early repolarization pattern (ERP) on the surface ECG is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait, but molecular genetic determinants are unknown. METHODS: To identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry. RESULTS: We identified a genome-wide significant (P < 5 × 10(–8)) locus in the potassium voltage-gated channel subfamily D member 3 (KCND3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discov…

Familial hypercholesterolaemia: A global call to arms

Familial Hypercholesterolaemia (FH) is the commonest autosomal co-dominantly inherited condition affecting man. It is caused by mutation in one of three genes, encoding the low-density lipoprotein (LDL) receptor, or the gene for apolipoprotein B (which is the major protein component of the LDL particle), or in the gene coding for PCSK9 (which is involved in the degradation of the LDL-receptor during its cellular recycling). These mutations result in impaired LDL metabolism, leading to life-long elevations in LDL-cholesterol (LDL-C) and development of premature atherosclerotic cardiovascular disease (ASCVD) [1], [2] and [3]. If left untreated, the relative risk of premature coronary artery d…

Mejora en la estratificación del riesgo tras el implante percutáneo de válvula aórtica mediante una combinación de marcador tumoral CA125 y EuroSCORE logístico

ResumenIntroduccion y objetivos El rendimiento de las puntuaciones de riesgo tradicionales para predecir el riesgo tras el implante percutaneo valvula aortica (TAVI) no es adecuado. Las altas concentraciones plasmaticas de antigeno carbohidrato 125 (CA125) se han asociado a un aumento del riesgo de eventos adversos tras TAVI. En este trabajo se evalua el valor pronostico adicional del CA125 sobre la puntuacion EuroSCORE para la prediccion de riesgo a largo plazo. Metodos y resultados Durante una mediana de seguimento de 59 semanas, murieron 115 de 422 pacientes (27%) despues de la TAVI. La mortalidad fue mayor entre aquellos con CA125 elevado (> 30 U/ml) y EuroSCORE ≥ mediana (el 47 frente …

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 &lt; 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 …

Comparison of Carbohydrate Antigen 125 and N-Terminal Pro-Brain Natriuretic Peptide for Risk Prediction After Transcatheter Aortic Valve Implantation

Elevated carbohydrate antigen 125 (CA125) and N-terminal pro-brain natriuretic peptide (NTproBNP) have been associated with adverse outcome after transcatheter aortic valve implantation (TAVI). This study performs a comparison of both biomarkers for prognosis after TAVI. The study includes 363 patients. The primary end point was all-cause death or readmission for worsening congestive heart failure within 1 year after TAVI, and this end point occurred in 16% of the population. The optimal cutoff to predict the primary end point was 18.4 U/ml for CA125 and 2,570 ng/L for NTproBNP. Elevated CA125 levels were present in 52% and were associated with a higher rate of the primary end point (27% vs…

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…

Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study

BACKGROUND: High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal. METHODS: We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20,913 myocardial infarction cases, 95,407 controls). Se…

Design of the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Study

Background— Recent genome-wide association studies (GWAS) of myocardial infarction (MI) and other forms of coronary artery disease (CAD) have led to the discovery of at least 13 genetic loci. In addition to the effect size, power to detect associations is largely driven by sample size. Therefore, to maximize the chance of finding novel susceptibility loci for CAD and MI, the Coronary ARtery DIsease Genome-wide Replication And Meta-analysis (CARDIoGRAM) consortium was formed. Methods and Results— CARDIoGRAM combines data from all published and several unpublished GWAS in individuals with European ancestry; includes &gt;22 000 cases with CAD, MI, or both and &gt;60 000 controls; and unifies …

P1590Percutaneous systemic av-valve repair for the treatment of severe tricuspid regurgitation in patients with congenitally corrected transposition of the great arteries

Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function

BACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication …

Cis-epistasis at the LPA locus and risk of cardiovascular diseases.

AIMS Coronary artery disease (CAD) has a strong genetic predisposition. However, despite substantial discoveries made by genome-wide association studies (GWAS), a large proportion of heritability awaits identification. Non-additive genetic-effects might be responsible for part of the unaccounted genetic variance. Here we attempted a proof-of-concept study to identify non-additive genetic effects, namely epistatic interactions, associated with CAD. METHODS AND RESULTS We tested for epistatic interactions in ten CAD case-control studies and UK Biobank with focus on 8,068 SNPs at 56 loci with known associations with CAD risk. We identified a SNP pair located in cis at the LPA locus, rs1800769 …

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…

P4.08 AUGMENTATION INDEX AND AORTIC DISEASE IN MARFAN-LIKE SYNDROMES