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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. In the WTCCC and the German MI Family studies, additional single-nucleotide polymorphisms in the LRP8 gene were analysed and displayed no evidence for association either. [ABSTRACT FROM AUTHOR]

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. Replication of association with LDL-C level was sought for the most significant single nucleotide polymorphism (SNP) within the LDLR gene in three European samples comprising 6 642 adults and 533 children. Association of this SNP with CAD was examined in six case-control studies involving more than 15 000 individuals. Findings: Each copy of the minor T allele of SNP rs2228671 within LDLR (frequency 11%) was related to a decrease of LDL-C levels by 0.19 mmol/L (95% confidence interval (CI) [0.13-0.24] mmol/L, p = 1.5×10-10). This association with LDL-C was uniformly found in children, men, and women of all samples studied. In parallel, the T allele of rs2228671 was associated with a significantly lower risk of CAD (Odds Ratio per copy of the T allele: 0.82, 95% CI [0.76-0.89], p = 2.1×10-7). Adjustment for LDL-C levels by logistic regression or Mendelian Randomisation models abolished the significant association between rs2228671 with CAD completely, indicating a functional link between the genetic variant at the LDLR gene locus, change in LDL-C and risk of CAD. Conclusion: A common variant at the LDLR gene locus affects LDL-C levels and, thereby, the risk for CAD. [ABSTRACT FROM AUTHOR]

In mice, dystrophic cardiovascular calcification (DCC) is controlled by a major locus on proximal mouse chromosome 7 named Dyscalc1. Here we present a strategy that combines in silico analysis, expression analysis, and extensive sequencing for ultrafine mapping of the Dyscalc1 locus. We subjected 15 laboratory mouse strains to freezethaw injury of the heart, and association with respective genotypes allowed condensation of the Dyscalc1 locus to 1 Mb. Within this region, 51 known and predicted genes were studied in DCC-susceptible C3H/He and DCC-resistant C57BL/6 mice with respect to mRNA expression in response to injury. Five genes displayed differential expression. Genotyping of seven novel single nucleotide polymorphisms (SNPs) within these genes revealed an 80-Kb region in NZB mice that were found positive for calcification though carrying otherwise alleles from DCC-resistant mice. This microheterogeneity in NZB mice was evolutionary conserved in all DCC-susceptible mouse strains and contains the genes EMP-3, BC013491, and Abcc6 (partially). The flanking SNPs are rs3703247 and NT_039420.5_2757991. mRNA levels of EMP-3 were found to be upregulated in response to injury in both C57BL/6 and C3H/He mice. Sequencing of EMP-3 revealed an SNP leading to an amino acid substitution (p.T153I) that was found in all mouse strains susceptible for DCC but not in resistant strains such as C57BL/6 mice. Thus, the p.T153I changes might affect the biological function of EMP-3 gene product after injury. Using this combined approach, we ultrafine-mapped the Dyscalc1 locus to an 80-Kb region and identified EMP-3 as a new candidate gene for DCC. [ABSTRACT FROM AUTHOR]

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. Two previously described four SNP (single nucleotide polymorphism) haplotypes of the ALOX5AP gene (termed haplotype A and B) and one SNP (rs2660899) of the LTA4H gene conferring the greatest risk of MI in previous studies were genotyped in 1211 unrelated MI cases from the German MI Family Study and in 1015 healthy married-in spouses serving as controls. Haplotype B in the ALOX5AP gene was associated with an increased risk of MI in the German population, confirming previously reported associations of this haplotype with CAD (coronary artery disease) in populations from Scotland and Italy. No association with the risk of MI was detected for haplotype A of the ALOX5AP gene or for SNP rs2660899 representing the LTA4H gene. In conclusion, haplotype B of the ALOX5AP gene is associated with an increased risk of MI in a large German study. The present study is the third independent report from a European population describing an increased risk of CAD for carriers of haplotype B of the ALOX5AP gene, which substantiates further a role of this gene in the pathogenesis of CAD in Europeans.

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., Methods and Results: A single-nucleotide polymorphism (SNP), rs1333049, representing the 9p21.3 locus, was genotyped in 7 case-control studies involving a total of 4645 patients with myocardial infarction or CAD and 5177 controls. The mode of inheritance was determined. In addition, in 5 of the 7 studies, we genotyped 3 additional SNPs to assess a risk-associated haplotype (ACAC). Finally, a meta-analysis of the present data and previously published samples was conducted. A limited fine mapping of the locus was performed. The risk allele (C) of the lead SNP, rs1333049, was uniformly associated with CAD in each study (P<0.05). In a pooled analysis, the odds ratio per copy of the risk allele was 1.29 (95% confidence interval, 1.22 to 1.37; P=0.0001). Haplotype analysis further suggested that this effect was not homogeneous across the haplotypic background (test for interaction, P=0.0079). An autosomal-additive mode of inheritance best explained the underlying association. The meta-analysis of the rs1333049 SNP in 12,004 cases and 28,949 controls increased the overall level of evidence for association with CAD to P=6.04x10(-10) (odds ratio, 1.24; 95% confidence interval, 1.20 to 1.29). Genotyping of 31 additional SNPs in the region identified several with a highly significant association with CAD, but none had predictive information beyond that of the rs1333049 SNP., Conclusions: This broad replication provides unprecedented evidence for association between genetic variants at chromosome 9p21.3 and risk of CAD.

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., Methods and Results: The MEF2A gene was sequenced in MI patients from 23 MI families (> or =5 affected members per family), but no mutation was identified in any of these extended families. Moreover, the Pro279Leu variant in exon 7 was analyzed in 1181 unrelated MI patients with a positive family history for MI/CAD, in 533 patients with sporadic MI, and in 2 control populations (n=1021 and n=1055), showing no evidence for association with MI/CAD. In addition, a (CAG)n repeat in exon 11 was genotyped in 543 sporadic MI patients and in 1190 controls without evidence for association with MI. Finally, analyzing 11 single-nucleotide polymorphisms from the GeneChip Mapping 500K Array, genotyped in 1644 controls and 753 cases, failed to provide evidence for association (region-wide P=0.23)., Conclusions: Studying independent samples of >1700 MI patients, 2 large control populations, and multiple families with apparently mendelian inheritance of the disease, we found no evidence for any linkage or association signal in the MEF2A gene.

Objectives: Coronary artery calcification (CAC) determined by electron beam computed tomography is a predictor of future cardiovascular events. This study investigates conditions affecting CAC severity in patients with coronary artery disease (CAD) undergoing coronary angiography., Methods: Presence and degree of CAC were assessed angiographically in 877 CAD patients grouped into no visible CAC (n = 333), mild to moderate CAC (n = 321), and severe CAC (n = 223). Regression analyses investigated relationships between CAC and demographic data, cardiovascular risk factors, and coronary anatomy., Results: Prevalences of hypertension and systolic blood pressure (SBP) values were higher in individuals with CAC (moderate CAC: 49.5%, 137.5 +/- 18.6 mmHg; severe CAC: 58.3%, 142.1 +/- 20.4 mmHg) compared to individuals with CAD but no CAC (42.0%, 134.0 +/- 18.4 mmHg; both P < 0.001). Likewise, pulse pressure was significantly elevated with increasing degree of CAC (no CAC, 52.3 +/- 13.6 mmHg vs moderate CAC, 55.7 +/- 14.4 mmHg vs severe CAC, 59.1 +/- 15.4 mmHg; P < 0.001). Further determinants of CAC were age, positive family history for CAC and severity of CAD. No differences in CAC severity were found in relation to body mass index, low-density lipoprotein-cholesterol, diabetes, and smoking habits. In multivariate analysis, CAC was independently related to age, SBP or pulse pressure, respectively, positive family history for CAC, and the severity of CAD., Conclusions: Of the cardiovascular risk factors, SBP and pulse pressure display the strongest relationship with angiographic detection of CAC. Mechanistic studies need to clarify whether hypertension causes CAC, or whether coronary calcium deposition serves as a marker for a higher degree of vascular calcification and, thus, impaired vascular compliance and higher blood pressure levels.

Genetic variants of the arachidonic acid monooxygenase CYP4A11 result in decreased synthesis of 20-hydroxyeicostatetraenoic acid and experimental hypertension. Moreover, in humans, the T8590C polymorphism of CYP4A11 displayed association with arterial hypertension. The aim of the present study was to further investigate this association in a large population-based sample. Therefore, the participants of the echocardiographic substudy of the third MONICA (MONitoring trends and determinants In CArdiovascular disease) survey (n=1397) were studied by standardized anthropometric, echocardiographic, and biochemical measurements as well as genotyping for CYP4A11 T8590C allele status. Individuals with the CC genotype have higher systolic (CC 141.4+/-3.17 mm Hg versus CT 134.2+/-0.97 mm Hg and TT 134.3+/-0.53 mm Hg; P=0.03) and diastolic blood pressure levels (CC 85.4+/-2.06 mm Hg versus CT 80.3+/-0.63 mm Hg and TT 80.7+/-0.34 mm Hg; P=0.02). Accordingly, the odds ratio (adjusted for age, body mass index, and gender) of the CC genotype versus the CT and TT genotypes for hypertension was 3.31 (95% confidence interval [CI]), 1.38 to 7.96; P=0.016) in the entire study population, with similar trends in men (4.30 [95% CI, 1.08 to 17.15]) and women (2.93 [95% CI, 0.88 to 9.84]). Consistent with the renal effects of the gene, no blood pressure-independent association between the T8590C polymorphism and echocardiographic parameters of left ventricular function and geometry was found. In conclusion, our data strengthen the association between the T8590C polymorphism of CYP4A11 and hypertension and suggest a recessive mode of inheritance. In contrast, we found no blood pressure-independent modulatory effect of CYP4A11 T8590C on cardiac size, structure, and function.