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Angiotensin-I converting enzyme (ACE) occupies a pivotal role in cardiovascular homeostasis. Major loci for plasma ACE have been identified at ACE on Chromosome 17 and at ABO on Chromosome 9. We sought to characterise the genetic architecture of plasma ACE at finer resolution in two populations. We carried out a GWAS in 1810 individuals of Japanese ethnicity; this identified signals at ACE and ABO that together accounted for nearly half of the population variability of the trait. We conducted measured haplotype analysis at the ABO locus in 1425 members of 248 British families using haplotypes of three SNPs, which together tagged the alleles responsible for the principal blood group antigens A1, A2, B and O. Type O alleles were associated with intermediate plasma ACE activity compared to Type A1 alleles (in whom plasma ACE activity was ~36% lower) and Type B alleles (in whom plasma ACE activity was ~36% higher). We demonstrated heterogeneity among A alleles: A2 alleles were associated with plasma ACE activity that was very similar to the O alleles. Variation at ACE accounted for 35% of the trait variance, and variation at ABO accounted for 15%. A further 10% could be ascribed to polygenic effects. [ABSTRACT FROM AUTHOR]

The article presents a study that clarifies the effects of aldosterone excess on myocardial structure and composition in human subjects with primary aldosteronism (PA). It found a significant increase in the frequency of noninfarct late gadolinium enhancement in PA. It illustrates that patients with PA exhibit frequent myocardial fibrosis.

Blockade of the MR (mineralocorticoid receptor) in CKD (chronic kidney disease) reduces LVMI [LV (left ventricular) mass index] and proteinuria. The MR can be activated by aldosterone, cortisol and DOC (deoxycorticosterone). The aim of the present study was to explore the influence of mineralocorticoids on LVMI and proteinuria in patients with CKD. A total of 70 patients with CKD and 30 patients with EH (essential hypertension) were recruited. Patients underwent clinical phenotyping; biochemical assessment and 24 h urinary collection for THAldo (tetrahydroaldosterone), THDOC (tetrahydrodeoxycorticosterone), cortisol metabolites (measured using GC-MS), and urinary electrolytes and protein [QP (proteinuira quantification)]. LVMI was measured using CMRI (cardiac magnetic resonance imaging). Factors that correlated significantly with LVMI and proteinuria were entered into linear regression models. In patients with CKD, significant predictors of LVMI were male gender, SBP (systolic blood pressure), QP, and THAldo and THDOC excretion. Significant independent predictors on multivariate analysis were THDOC excretion, SBP and male gender. In EH, no association was seen between THAldo or THDOC and LVMI; plasma aldosterone concentration was the only significant independent predictor. Significant univariate determinants of proteinuria in patients with CKD were THAldo, THDOC, USod (urinary sodium) and SBP. Only THAldo excretion and SBP were significant multivariate determinants. Using CMRI to determine LVMI we have demonstrated that THDOC is a novel independent predictor of LVMI in patients with CKD, differing from patients with EH. Twenty-four hour THAldo excretion is an independent determinant of proteinuria in patients with CKD. These findings emphasize the importance of MR activation in the pathogenesis of the adverse clinical phenotype in CKD. [ABSTRACT FROM AUTHOR]

Objective: The combined thickness of the intima and media of the carotid artery (carotid intima-medial thickness, CIMT) is associated with cardiovascular disease and stroke. Previous studies indicate that carotid intima-medial thickness is a significantly heritable phenotype, but the responsible genes are largely unknown. Hexose-6 phosphate dehydrogenase (H6PDH) is a microsomal enzyme whose activity regulates corticosteroid metabolism in the liver and adipose tissue; variability in measures of corticosteroid metabolism within the normal range have been associated with risk factors for cardiovascular disease. We performed a genetic association study in 854 members of 224 families to assess the relationship between polymorphisms in the gene coding for hexose-6 phosphate dehydrogenase (H6PD) and carotid intima-medial thickness. Methods: Families were ascertained via a hypertensive proband. CIMT was measured using B-mode ultrasound. Single nucleotide polymorphisms (SNPs) tagging common variation in the H6PD gene were genotyped. Association was assessed following adjustment for significant covariates including ''classical'' cardiovascular risk factors. Functional studies to determine the effect of particular SNPs on H6PDH were performed. Results: There was evidence of association between the single nucleotide polymorphism rs17368528 in exon five of the H6PD gene, which encodes an amino-acid change from proline to leucine in the H6PDH protein, and mean carotid intimamedial thickness (p = 0.00065). Genotype was associated with a 5% (or 0.04 mm) higher mean carotid intima-medial thickness measurement per allele, and determined 2% of the population variability in the phenotype. Conclusions: Our results suggest a novel role for the H6PD gene in atherosclerosis susceptibility. [ABSTRACT FROM AUTHOR]

The article discusses a study which determined the association of common variation at the 11-β hydroxysteroid dehydrogenase type 1 gene with obesity-related cardiovascular risk factors, including hypertension and type II diabetes. It describes the measurement of left ventricular mass (LVM) through echocardiography and electrocardiography. It also illustrates the single-nucleotide polymorphisms (SNPs) genotyped in the 11-β hydroxysteroid dehydrogenase type 1 gene.

Primary aldosteronism (PA) is common with an estimated prevalence rate of 10% in subjects with essential hypertension and higher in those with resistant hypertension. As well as contributing to hypertension, aldosterone has detrimental effects on the heart, vasculature and kidneys as well as adverse metabolic effects leading to an excess of cardiovascular morbidity. Therefore, recognition and appropriate treatment of PA is of increasing importance. However, the diagnosis of PA and determination of subtype can be problematic. The purpose of this review is to provide an overview of the evidence supporting this increased prevalence of PA, explore the metabolic and cardiovascular consequences of aldosterone excess and discuss optimal diagnostic and therapeutic strategies of PA. INSET: Key issues. [ABSTRACT FROM AUTHOR]

There is a linear relationship between resting heart rate (HR) and mortality in normotensive and untreated hypertensive individuals. However, it is not clear whether HR is a marker of increased risk in hypertensive patients on treatment. We investigated the relationship between HR and mortality in patients with hypertension. We analyzed baseline HR, final HR, and HR change during follow-up in patients attending the Glasgow Blood Pressure Clinic. Using a threshold of 80 bpm, we classified patients into those who had a consistently high (high-high) or low (low-low) HR or patients whose HR increased (low-high) or decreased (high-low) over time. Survival analysis was carried out using Cox proportional hazards models adjusted for age, sex, body mass index, smoking, rate-limiting therapy, systolic blood pressure, and serum cholesterol. For each beat of HR change there was a 1% change in mortality risk. The highest risk of an all-cause event was associated with patients who had increased their HR by >or=5 bpm at the end of follow-up (1.51 [95% CI: 1.03 to 2.20]; P=0.035). Compared with low-low patients, high-high patients had a 78% increase in the risk of all-cause mortality (HR: 1.78 [95% CI: 1.31 to 2.41]; P<0.001). Cardiovascular mortality showed a similar pattern of results. Rate-limiting therapy did not have an independent effect on outcomes in this analysis. Change in HR achieved during follow-up of hypertensive patients is a better predictor of risk than baseline or final HR. After correction for rate-limiting therapy, HR remained a significant independent risk factor. [ABSTRACT FROM AUTHOR]

The -344 C/T and intron 2 conversion variants in the CYP11B2 gene, encoding aldosterone synthase, have been associated with markers of impaired 11beta-hydroxylase activity. We hypothesize that this association is because of variations in the adjacent 11beta-hydroxylase gene (CYP11B1) and arises through linkage disequilibrium between CYP11B1 and CYP11B2. The pattern of variation across the entire CYP11B locus was determined by sequencing 26 normotensive subjects stratified by and homozygous for the -344 and intron conversion variants. Eighty-three variants associated with -344 and intron conversion were identified. Haplotype analysis revealed 4 common haplotypes, accounting for 68% of chromosomes, confirming strong linkage disequilibrium across the region. Two novel CYP11B1 polymorphisms upstream of the coding region (-1889 G/T and -1859 A/G) were identified as contributing to the common haplotypes. Given the potential for such mutations to affect transcriptional regulation of CYP11B1, these were analyzed further. A total of 512 hypertensive subjects from the British Genetics of Hypertension Study population were genotyped for these polymorphisms. A significant association was identified between the -1889 polymorphism and urinary tetrahydrodeoxycortisol/total cortisol metabolite ratio, indicating reduced 11beta-hydroxylase efficiency. A similar pattern was observed for the -1859 polymorphism, but this did not achieve statistical significance. Functional studies in vitro using luciferase reporter gene constructs show that these polymorphisms significantly alter the transcriptional response of CYP11B1 to stimulation by adrenocorticotropic hormone or forskolin. This study strongly suggests that the impaired 11beta-hydroxylase efficiency associated previously with the CYP11B2 -344 and intron conversion variants is because of linkage with these newly identified polymorphisms in CYP11B1. [ABSTRACT FROM AUTHOR]

Rare mutations in the proopiomelanocortin (POMC) gene cause severe early-onset childhood obesity. However, it is unknown whether common variants in POMC are responsible for variation in body weight or fat distribution within the commonly observed range in the population. We tested for association between three polymorphisms spanning the POMC gene and obesity phenotypes in 1,428 members of 248 families. There was significant association between genotypes at the C8246T (P < 0.0001) and C1032G (P = 0.003) polymorphisms and waist-to-hip ratio (WHR) corrected for age, sex, smoking, exercise, and alcohol consumption. Each T allele at C8246T (or G allele at C1032G) was associated with a 0.2-SD-higher WHR in a codominant fashion. When WHR was additionally corrected for BMI, thus providing a measure of body fat distribution throughout the range of BMI, there remained significant evidence for association with both markers that was of similar magnitude and statistical significance. There was no association between genotype at any polymorphism and BMI or plasma leptin level. These data show that genetic variants at the POMC locus influence body fat distribution within the normal range, suggesting a novel role for POMC in metabolic regulation. Diabetes 54:2492-2496, 2005 [ABSTRACT FROM AUTHOR]