This broad replication provides unprecedented evidence for association between genetic variants at chromosome 9p21.3 and risk of CAD.

BackgroundRare 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.MethodsImputed 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.FindingsEach 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.ConclusionA common variant at the LDLR gene locus affects LDL-C levels and, thereby, the risk for CAD.

Angiotensin-converting enzyme (ACE) activity is considered to be of major importance for the conversion of angiotensin (Ang) I to Ang II. Recently, a second ACE, named ACE2, has been identified. Experimental data provide evidence that ACE2 might be involved in modulating cardiac structure and function. In the present explorative study, we assessed whether polymorphisms in the ACE2 gene are related to echocardiographically determined parameters of left ventricular mass, structure or function in the general population. Five intronic single nucleotide polymorphisms (SNPs) were genotyped using the 5'-exonuclease activity (TaqMan) assay in the echocardiographic substudy of the third MONICA Augsburg survey. As ACE2 is located on the X chromosome, women and men were analysed separately. Four SNPs showed high pairwise linkage disequilibrium (rs4646156, rs879922, rs4240157 and rs233575). The minor alleles of these four SNPs were associated with higher left ventricular mass index (LVMI) and higher septal wall thickness (SWT) in men. Likewise, male carriers of a common haplotype (frequency 29.9%) consisting of the minor alleles of these four SNPs displayed higher values for LVMI and SWT than non-carriers (LVMI: TGGC 98.8+/-1.52 vs non-TGGC 94.8+/-0.99 g/m(2), p=0.027; SWT: TGGC 11.5+/-0.14 vs non-TGGC 11.1+/-0.09 mm, p=0.019). Furthermore, this haplotype was associated with an increased odds ratio (OR) for left ventricular hypertrophy (OR 3.10, p=0.006). In women, similar but less pronounced and consistent trends were observed. No association was observed between any of these SNPs and parameters of left ventricular systolic or diastolic function nor with blood pressure levels. This study provides evidence that genetic variants in the ACE2 gene may be associated with left ventricular mass, SWT and left ventricular hypertrophy in hemizygous men.

Abstract-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 (nϭ1397) were studied by standardized anthropometric, echocardiographic, and biochemical measurements as well as genotyping for CYP4A11 . 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. Key Words: genetics Ⅲ polymorphism Ⅲ hypertension, arterial Ⅲ echocardiography A variety of gene variants has shown association with arterial hypertension. However, only small or inconsistent effects on blood pressure were observed for most of the frequent polymorphisms of hypertension-related genes. 1 On the other hand, mutations with profound implications for blood pressure regulation were found predominantly in exceptional families. 2 Thus, despite extensive research, genetic testing for risk assessment in hypertension is not yet advisable for routine patient evaluation. A major challenge for this field will be the identification of genetic variants with reproducible and clinically as well as epidemiologically relevant effects on blood pressure regulation that, in addition, offer the potential of therapeutical intervention.The CYP4A arachidonic acid monooxygenase oxidizes endogenous arachidonic acid to 20-hydroxyeicostatetraenoic acid (20-HETE). Depending on its expression at renovascular or tubular sites, the 20-HETE metabolite can act in a prohypertensive or antihypertensive manner. [3][4][5][6] Holla et al characterized a CYP4A14 (Ϫ/Ϫ) knockout mouse as a model of gender-specific severe hypertension. 7 Evaluation of human homologues as potential novel genetic determinants in hypertension revealed 2 candidate genes: CYP4A11 and CYP4A22 from the CYP4A gene family. 8,9 Recently, CYP4A11 but not CYP4A22 was identified as the functional active protein that catalyzes the metabolism of arachidonic acid to 20-HETE in humans. 10 Screening for genetic variants revealed a cytosine for thymidine transition at nucleotide 8590 in exon 11, which results in a nonsynonymous phenylalanine to serine substitution at residue 434 of CYP4A11. The less frequent 8590C genotype, which corresponds to the 434S variant on protein

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. We genotyped 2,037 adult individuals from 520 nuclear families characterised for body mass index, waist-hip ratio, 24-h ambulatory blood pressure, total cholesterol, high-density lipoprotein cholesterol and glucose for the lead single nucleotide polymorphisms (SNPs) in the seven CAD-associated loci. SNP rs599839, representing the locus in the vicinity of the PSRC1 and CELSR2 genes on chromosome 1p13.3, showed a strong association with total cholesterol. The CAD-associated risk allele A of rs599839 (allele frequency 0.78) was associated with a 0.17-mmol/l (95% CI 0.10 to 0.24 mmol/l) higher serum cholesterol level per allele copy (P = 3.84 x 10(-6)). The association of the A allele with higher total cholesterol was confirmed in an independent cohort (n = 847) of healthy adults (P = 1.0 x 10(-4)) and related to an effect on low-density lipoprotein (LDL) cholesterol (P = 8.56 x 10(-5)). An association of rs599839 with LDL cholesterol was also shown in 1,090 cases with myocardial infarction (P = 0.0026). None of the other variants showed a strong association with the measured cardiovascular risk factors, suggesting that these loci act through other mechanisms. However, the novel CAD-associated locus in the vicinity of the PSRC1 and CELSR2 genes on chromosome 1 probably enhances CAD risk through an effect on plasma LDL cholesterol. The findings support further investigation of the role of these genes in cholesterol metabolism and coronary risk.

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.

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 (≥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.

The data obtained in the present study strengthen the evidence of an association of the CYP4A11 T8590C polymorphism with blood pressure levels and hypertension prevalence. Particularly, the risk of arterial hypertension is substantially higher in MI patients homozygous for the CC allele. By contrast, no evidence was obtained for an association between this genotype and MI.