Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies.

Background: We tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis.

Methods: We did two genome-wide association studies (GWAS) with coronary angiographic phenotyping in participants of European ancestry. To identify loci that predispose to angiographic coronary artery disease (CAD), we compared individuals who had this disorder (n=12,393) with those who did not (controls, n=7383).

Genome-wide association study identifies a new locus for coronary artery disease on chromosome 10p11.23.

Aims: Recent genome-wide association (GWA) studies identified 10 chromosomal loci for coronary artery disease (CAD) or myocardial infarction (MI). However, these loci explain only a small proportion of the genetic variability of these pertinent diseases. We sought to identify additional CAD/MI loci by applying a three-stage approach.

Genetic causes of myocardial infarction: new insights from genome-wide association studies.

Background: A positive family history for myocardial infarction (MI) is known to be a major cardiovascular risk factor. The current European guidelines therefore recommend intensified primary prevention for the siblings and children of persons who have had an MI. Although the genes underlying the heritable component of MI were largely unknown previously, the development of new molecular genetic methods, and particularly the advent of genome-wide association (GWA) studies, has led to the discovery of numerous genetic variants that are associated with an elevated risk of MI.

Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM.

Lack of association between the Trp719Arg polymorphism in kinesin-like protein-6 and coronary artery disease in 19 case-control studies.

Objectives: We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD).

Background: Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers.

Methods: The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports.

Genetic regulation of serum phytosterol levels and risk of coronary artery disease.

Background: Phytosterols are plant-derived sterols that are taken up from food and can serve as biomarkers of cholesterol uptake. Serum levels are under tight genetic control. We used a genomic approach to study the molecular regulation of serum phytosterol levels and potential links to coronary artery disease (CAD).

Physicians' perception of guideline-recommended low-density lipoprotein target values: characteristics of misclassified patients.

Aims: The present study investigated the awareness of primary care physicians for patient characteristics relevant for designation of low-density lipoprotein (LDL) target values.

Methods And Results: Physicians (n = 907) were asked to estimate guideline-recommended LDL target value for 30 of their patients with hyperlipidaemia. In total, 25 250 patients were allocated on that basis in three different groups (LDL target <100, <130, and <160 mg/dL), in which by guideline criteria 68.

Association of the single nucleotide polymorphism rs599839 in the vicinity of the sortilin 1 gene with LDL and triglyceride metabolism, coronary heart disease and myocardial infarction. The Ludwigshafen Risk and Cardiovascular Health Study.

Objective: The rs599839 polymorphism A/G in the vicinity of the sortilin 1 gene has been reported to be associated with low density lipoprotein cholesterol (LDL-C) and coronary artery disease (CAD). The objective of this study was to further characterize the protective effect of the minor allele by analyzing the association with a variety of quantitative traits.

Methods: Association of rs599839 with plasma levels of different parameters of LDL and triglyceride (TRIG) metabolism as well as the risk of CAD was tested in the LURIC study cohort.

Genetic variation at chromosome 1p13.3 affects sortilin mRNA expression, cellular LDL-uptake and serum LDL levels which translates to the risk of coronary artery disease.

Background: A single nucleotide polymorphism (SNP) rs599839 located at chromosome 1p13.3 has previously been associated with risk of coronary artery disease (CAD) and with serum levels of low-density lipoprotein cholesterol (LDL-C). A functional link explaining the association of SNP rs599839 with LDL-C levels and CAD risk has not yet been elucidated.

Association between degenerative aortic valve disease and long-term exposure to cardiovascular risk factors: results of the longitudinal population-based KORA/MONICA survey.

Aims: Degenerative aortic valve disease (DAVD), a common finding in the elderly, is associated with an increased risk of death due to cardiovascular causes. Taking advantage of its longitudinal design, this study evaluates the prevalence of DAVD and its temporal associations with long-term exposure to cardiovascular risk factors in the general population.

Methods And Results: We studied 953 subjects (aged 25-74 years) from a random sample of German residents.

Macrophage cholesterol efflux correlates with lipoprotein subclass distribution and risk of obstructive coronary artery disease in patients undergoing coronary angiography.

Background: Studies in patients with low HDL have suggested that impaired cellular cholesterol efflux is a heritable phenotype increasing atherosclerosis risk. Less is known about the association of macrophage cholesterol efflux with lipid profiles and CAD risk in normolipidemic subjects. We have therefore measured macrophage cholesterol efflux in 142 normolipidemic subjects undergoing coronary angiography.

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.

Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease.

We identify the SLC22A3-LPAL2-LPA gene cluster as a strong susceptibility locus for coronary artery disease (CAD) through a genome-wide haplotype association (GWHA) study. This locus was not identified from previous genome-wide association (GWA) studies focused on univariate analyses of SNPs. The proposed approach may have wide utility for analyzing GWA data for other complex traits.

Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants.

We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls. We carried out replication in an independent sample with an effective sample size of up to 19,492. SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9).

Lack of association between a common polymorphism near the INSIG2 gene and BMI, myocardial infarction, and cardiovascular risk factors.

Epidemiological studies revealed an increasing prevalence of and a steep increase in obesity, a risk factor for cardiovascular disease. Because significant influence of a polymorphism, rs7566605, near the INSIG2 gene on BMI has been shown in the general population and in obesity cohorts, we hypothesized that this polymorphism might also act through an elevated BMI on the development of coronary artery disease (CAD) or myocardial infarction (MI). We pursued two strategies: First, the polymorphism rs7566605 was investigated for association with BMI, CAD/MI, and cardiovascular risk factors in a large German cohort at high risk for CAD and MI (n = 1,460 MI patients) as compared to unrelated healthy controls (n = 1,215); second, we extended our analyses on the families of MI patients and performed family-based association testing (n = 5,390 individuals).

Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease--a Mendelian Randomisation study.

Background: Rare mutations of the low-density lipoprotein receptor gene (LDLR) cause familial hypercholesterolemia, which increases the risk for coronary artery disease (CAD). Less is known about the implications of common genetic variation in the LDLR gene regarding the variability of cholesterol levels and risk of CAD.

Methods: Imputed genotype data at the LDLR locus on 1 644 individuals of a population-based sample were explored for association with LDL-C level.

The novel genetic variant predisposing to coronary artery disease in the region of the PSRC1 and CELSR2 genes on chromosome 1 associates with serum cholesterol.

Through genome-wide association studies, we have recently identified seven novel loci that confer a substantial increase in risk for coronary artery disease (CAD). Elucidating the mechanisms by which these loci affect CAD risk could have important clinical utility. Here, we investigated whether these loci act through mechanisms involving traditional cardiovascular risk factors.

Lack of association of genetic variants in the LRP8 gene with familial and sporadic myocardial infarction.

Coronary artery disease (CAD) and myocardial infarction (MI) have a genetic basis, but the precise genetic underpinning remains controversial. Recently, an association of the LRP8 R952Q polymorphism (rs5174) with familial premature CAD/MI was reported. We analysed rs5174 (or the perfect proxy rs5177) in 1,210 patients with familial MI and 1,015 controls from the German MI Family study, in 1,926 familial CAD (1,377 with MI) patients and 2,938 controls from the Wellcome Trust Case Control Consortium (WTCCC) MI/CAD cohort, in 346 CAD patients and 351 controls from the AtheroGene study and in 295 men with incident CAD and 301 controls from the Prospective Epidemiological Study of MI study and found no evidence for association in any of the populations studied.

Repeated replication and a prospective meta-analysis of the association between chromosome 9p21.3 and coronary artery disease.

Background: Recently, genome-wide association studies identified variants on chromosome 9p21.3 as affecting the risk of coronary artery disease (CAD). We investigated the association of this locus with CAD in 7 case-control studies and undertook a meta-analysis.

Genetic variation in the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) is associated with myocardial infarction in the German population.

Genetic variation in the genes ALOX5AP (arachidonate 5-lipoxygenase-activating protein) and LTA4H (leukotriene A4 hydrolase) has previously been shown to contribute to the risk of MI (myocardial infarction) and stroke in Icelandic and Scottish populations. Both genes encode proteins playing a role in the synthesis of the pro-inflammatory leukotriene B mediators, possibly providing a link between MI and inflammation. The aim of the present study was to investigate whether these associations could be confirmed in a large study of German MI patients.

An alternative splice variant in Abcc6, the gene causing dystrophic calcification, leads to protein deficiency in C3H/He mice.

Dystrophic cardiac calcification (DCC) is an autosomal recessive trait characterized by calcium phosphate deposits in myocardial tissue. The Abcc6 gene locus was recently found to mediate DCC; however, at the molecular level the causative variants remain to be determined. Examining the sequences of Abcc6 cDNA in DCC-resistant C57BL/6 and DCC-susceptible C3H/He mice, we identified a missense mutation (Cys to Thr at codon 619, rs32756904) at the 3'-border of exon 14 that creates an additional donor splice site (GT).

Lack of association between the MEF2A gene and myocardial infarction.

Background: Coronary artery disease (CAD) and myocardial infarction (MI) are caused in part by genetic factors. Recently, the MEF2A gene was linked to MI/CAD in a single pedigree with autosomal-dominant pattern of inheritance. In addition, genetic variants within the gene have been associated with MI in case-control settings, producing inconsistent results.

Association of a functional polymorphism in the CYP4A11 gene with systolic blood pressure in survivors of myocardial infarction.

Objective: Survivors of myocardial infarction (MI) are known to have a high prevalence of arterial hypertension which, at the same time, imposes a major risk to such patients. Genetic variants of the arachidonic acid monooxygenase CYP4A11 may result in decreased synthesis of 20-hydroxyeicostatetraenoic acid (20-HETE), experimental hypertension and elevated blood pressure levels in humans. The present study aimed to investigate the impact of the functionally relevant T8590C polymorphism of this gene on blood pressure and the prevalence of hypertension in MI patients.