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1.
Clin Endocrinol (Oxf) ; 83(5): 629-35, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26053152

ABSTRACT

OBJECTIVE: Steroid 11ß-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia. Nonclassic or mild 11OHD appears to be a rare condition. Our study assessed the residual CYP11B1 function of detected mutations, adding to the spectrum of mild 11OHD, and illustrates the variability of the clinical presentation of 11OHD. PATIENTS AND METHODS: Five patients presented with mild to moderate 11OHD. Two women presented with mild hirsutism and in one case with secondary amenorrhoea. Two men presented with precocious pseudopuberty, gynaecomastia and elevated blood pressure. One 46,XX female patient was diagnosed with virilization of the external genitalia 2 years after birth. Direct DNA sequencing was carried out to perform CYP11B1 mutation analysis. The CYP11B1 mutations were functionally characterized using an in vitro expression system. RESULTS: CYP11B1-inactivating mutations were detected in all patients. Two novel missense mutations (p.P42L and p.A297V) and the previously characterized p.R143W mutation had residual CYP11B1 activities between 10% and 27%. A novel p.L382R and the previously uncharacterized p.G444D mutation both caused complete loss of CYP11B1 enzymatic activity. CONCLUSION: Mutations causing partial impairment of 11ß-hydroxylase activity (residual activity of 10% or above) are associated with a less severe clinical presentation of 11OHD, which can be classified as a nonclassic form. Our data demonstrate that patients with nonclassic 11OHD can present with androgen excess, precocious pseudopuberty and increased blood pressure. Timely diagnosis of nonclassic 11OHD and consequently initiation of personalized treatment is essential to prevent co-morbidities caused by androgen excess and hypertension.


Subject(s)
Adrenal Hyperplasia, Congenital/genetics , Steroid 11-beta-Hydroxylase/genetics , Adult , Female , Humans , Male , Mutation , Young Adult
2.
Ann Hum Genet ; 77(6): 465-71, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23937567

ABSTRACT

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.


Subject(s)
ABO Blood-Group System/genetics , Alleles , Genetic Heterogeneity , Peptidyl-Dipeptidase A/blood , Peptidyl-Dipeptidase A/genetics , Quantitative Trait Loci , Enzyme Activation , Gene Frequency , Genetic Association Studies , Genome-Wide Association Study , Genotype , Haplotypes , Humans , Japan , Phenotype , Polymorphism, Single Nucleotide , White People/genetics
3.
Nephrol Dial Transplant ; 28(6): 1526-32, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23413088

ABSTRACT

BACKGROUND: Blockade of the mineralocorticoid receptor (MR) in patients with chronic kidney disease (CKD) improves surrogate cardiovascular outcomes, such as left ventricular mass. Animal models of renal disease support a pathological role of mineralocorticoids, in the context of a high sodium intake. We aimed to assess the regulation of mineralocorticoid biosynthesis in patients with CKD. METHODS: Seventy patients with CKD stages 3/4 and 30 patients with essential hypertension (EH) were recruited. Patients underwent detailed clinical phenotyping, drug history and biochemical assessment. Patients completed a 24-h urine collection for measurement of urinary tetrahydroaldosterone (THALDO) and tetrahydrocorticosterone (THDOC) excretion rates (measured using gas chromatography-mass spectrometry) and urinary electrolytes. The factors which correlated significantly with THALDO and THDOC excretion were entered into linear regression models. RESULTS: Patients with EH and CKD were well matched with no significant differences in gender, age or weight. The mean estimated glomerular filtration rate (eGFR) in CKD patients was 38.6/min/1.73 m(2). The mean urinary excretion rates of THALDO, THDOC and 24-h urinary sodium (24-h USod) were not significantly different between CKD and EH patients. The level of renal function did not correlate with THALDO or THDOC excretion. In patients with CKD, 24-h USodium (r = 0.614, P < 0.001) and 24-h UPotassium (r = 0.538, P < 0.001) were positively correlated with THALDO excretion. On multivariate linear regression analysis, 24-h USod was the strongest independent predictor (P = 0.004) of THALDO and THDOC excretion in CKD. In patients with EH, no relationship was seen between mineralocorticoid excretion and 24-h urinary sodium excretion. CONCLUSIONS: In patients with CKD, 24-h urinary sodium excretion is the strongest positive predictor of urinary mineralocorticoid excretion. The nature of this relationship is unexpected, novel, not seen in patients with EH and may explain the association seen between high urinary sodium excretion, mineralocorticoids and poor outcomes in patients with CKD.


Subject(s)
Aldosterone/analogs & derivatives , Corticosterone/analogs & derivatives , Hypertension/urine , Mineralocorticoids/urine , Renal Insufficiency, Chronic/urine , Sodium/urine , Aldosterone/urine , Cohort Studies , Corticosterone/urine , Cross-Sectional Studies , Essential Hypertension , Female , Gas Chromatography-Mass Spectrometry , Glomerular Filtration Rate , Humans , Male , Middle Aged , Prognosis
4.
Circ Cardiovasc Imaging ; 5(6): 740-7, 2012 Nov.
Article in English | MEDLINE | ID: mdl-23019275

ABSTRACT

BACKGROUND: Primary aldosteronism (PA) is common and associates with excess cardiovascular morbidity independent of blood pressure. Exposure to aldosterone and sodium leads to cardiac fibrosis and hypertrophy in humans and animals possibly mediated by inflammation and oxidative stress. We aimed to clarify the effects of aldosterone excess on myocardial structure and composition in human subjects with PA and essential hypertension using contrast-enhanced cardiac magnetic resonance imaging as well as explore the mechanistic basis for any observed differences. METHODS AND RESULTS: Twenty-seven subjects with recently diagnosed PA and 54 essential hypertension controls were recruited. Subjects underwent gadolinium-enhanced cardiac magnetic resonance; noninfarct related myocardial fibrosis was identified by a diffuse pattern of late gadolinium enhancement. Patients also underwent assessment of pulse wave velocity, measurement of circulating superoxide anion and C-reactive protein, as well as blood pressure and biochemical assessment. Subjects were well matched with no difference in severity or duration of hypertension. There was a significant increase in the frequency of noninfarct late gadolinium enhancement in PA (70%) when compared with essential hypertension subjects (13%; P<0.0001) with no difference in left ventricular mass. Pulse wave velocity, superoxide, and C-reactive protein were significantly higher in subjects with PA. CONCLUSIONS: These data illustrate that patients with PA exhibit frequent myocardial fibrosis as demonstrated by late gadolinium enhancement using cardiac magnetic resonance imaging; this finding is independent of blood pressure. This may be mediated partly through inflammation and oxidative stress. This study highlights the importance of specific targeting of aldosterone excess as well as blood pressure reduction to minimize cardiac morbidity in PA.


Subject(s)
Blood Pressure , Cardiomyopathies/etiology , Hyperaldosteronism/complications , Magnetic Resonance Imaging, Cine/methods , Myocardium/pathology , Cardiomyopathies/diagnosis , Cardiomyopathies/physiopathology , Female , Fibrosis/diagnosis , Fibrosis/etiology , Humans , Hyperaldosteronism/physiopathology , Male , Middle Aged
5.
Clin Sci (Lond) ; 123(5): 285-94, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22397469

ABSTRACT

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.


Subject(s)
Aldosterone/analogs & derivatives , Desoxycorticosterone/analogs & derivatives , Hypertrophy, Left Ventricular/etiology , Proteinuria/etiology , Renal Insufficiency, Chronic/complications , Aged , Aldosterone/urine , Biomarkers/urine , Cross-Sectional Studies , Desoxycorticosterone/urine , Female , Gas Chromatography-Mass Spectrometry , Humans , Hypertension/complications , Hypertension/urine , Hypertrophy, Left Ventricular/urine , Linear Models , Magnetic Resonance Imaging , Male , Middle Aged , Multivariate Analysis , Proteinuria/urine , Renal Insufficiency, Chronic/urine , Sex Factors
6.
Mol Cell Endocrinol ; 350(2): 163-7, 2012 Mar 24.
Article in English | MEDLINE | ID: mdl-21767599

ABSTRACT

Advances in the sensitivity of molecular techniques during the 1990s led to a flurry of studies that supported the existence of extra-adrenal sites of aldosterone production in various tissues including the brain and the heart. Subsequent work was often conflicting or ambiguous, leading many to question whether extra-adrenal aldosterone was of any physiological importance, or whether it even existed. In this article, we review these studies and, in light of this evidence, discuss whether the current lack of interest in extra-adrenal aldosterone biosynthesis is justified.


Subject(s)
Aldosterone/biosynthesis , Adipose Tissue/metabolism , Adipose Tissue/physiology , Adrenal Glands/metabolism , Adrenal Glands/physiology , Animals , Cardiovascular Physiological Phenomena , Cardiovascular System/metabolism , Central Nervous System/metabolism , Central Nervous System/physiology , Humans , Kidney/metabolism , Kidney/physiology
7.
Eur J Heart Fail ; 13(12): 1305-13, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21940729

ABSTRACT

AIMS: Mineralocorticoid receptor (MR) antagonists improve cardiovascular outcomes in patients with heart failure complicating acute myocardial infarction (AMI) and in chronic heart failure. It is unclear whether these beneficial effects are due solely to aldosterone blockade, as MR has a similar affinity for cortisol. We examined the relationships between plasma and urinary steroid hormones and left ventricular (LV) remodelling in patients with LV dysfunction following AMI. METHODS AND RESULTS: Plasma concentrations of renin, aldosterone, and N-terminal pro-brain natriuretic peptide (NT-proBNP), and 24 h urinary excretion rates of tetrahydroaldosterone (THAldo) and total cortisol metabolites were measured in 93 patients at a mean of 46 h following AMI prior to contrast-enhanced cardiac magnetic resonance (ceCMR). Patients were then randomized to 24 weeks of placebo or eplerenone therapy in addition to standard treatment, after which ceCMR was repeated. In placebo-treated patients, aldosterone, NT-proBNP, and excretion rates of THAldo and total cortisol metabolites were univariate predictors of remodelling (i.e. change in LV end-systolic volume index); aldosterone (P = 0.040) and total cortisol metabolite excretion (P = 0.038) remained independent predictors on multivariate analysis. None of the measured biomarkers predicted remodelling in the presence of eplerenone. Plasma and urinary aldosterone measures, and urinary cortisol metabolites, were not only related to larger infarct volumes and greater infarct remodelling over time, but were also higher in patients with microvascular obstruction on baseline ceCMR. CONCLUSION: Aldosterone and cortisol are associated with medium-term LV remodelling when measured early after AMI. The beneficial effects of MR antagonism may relate to blockade of both aldosterone- and cortisol-induced MR activation.


Subject(s)
Aldosterone/metabolism , Hydrocortisone/metabolism , Mineralocorticoid Receptor Antagonists/therapeutic use , Myocardial Infarction/metabolism , Spironolactone/analogs & derivatives , Ventricular Dysfunction, Left/etiology , Ventricular Remodeling/drug effects , Biomarkers/blood , Biomarkers/urine , Double-Blind Method , Echocardiography , Electrocardiography , Eplerenone , Female , Follow-Up Studies , Heart Ventricles/diagnostic imaging , Heart Ventricles/pathology , Heart Ventricles/physiopathology , Humans , Magnetic Resonance Imaging, Cine , Male , Middle Aged , Myocardial Infarction/complications , Myocardial Infarction/drug therapy , Prospective Studies , Spironolactone/therapeutic use , Time Factors , Treatment Outcome , Ventricular Dysfunction, Left/physiopathology , Ventricular Dysfunction, Left/prevention & control
8.
Biochem Biophys Res Commun ; 412(4): 747-51, 2011 Sep 09.
Article in English | MEDLINE | ID: mdl-21871446

ABSTRACT

Insulin stimulates endothelial NO synthesis, at least in part mediated by phosphorylation and activation of endothelial NO synthase at Ser1177 and Ser615 by Akt. We have previously demonstrated that insulin-stimulated NO synthesis is inhibited under high culture glucose conditions, without altering Ca(2+)-stimulated NO synthesis or insulin-stimulated phosphorylation of eNOS. This indicates that stimulation of endothelial NO synthase phosphorylation may be required, yet not sufficient, for insulin-stimulated nitric oxide synthesis. In the current study we investigated the role of supply of the eNOS substrate, L-arginine as a candidate parallel mechanism underlying insulin-stimulated NO synthesis in cultured human aortic endothelial cells. Insulin rapidly stimulated L-arginine transport, an effect abrogated by incubation with inhibitors of phosphatidylinositol-3'-kinase or infection with adenoviruses expressing a dominant negative mutant Akt. Furthermore, supplementation of endothelial cells with extracellular L-arginine enhanced insulin-stimulated NO synthesis, an effect reversed by co-incubation with the L-arginine transport inhibitor, L-lysine. Basal L-arginine transport was significantly increased under high glucose culture conditions, yet insulin-stimulated L-arginine transport remained unaltered. The increase in L-arginine transport elicited by high glucose was independent of the expression of the cationic amino acid transporters, hCAT1 and hCAT2 and not associated with any changes in the activity of ERK1/2, Akt or protein kinase C (PKC). We propose that rapid stimulation of L-arginine transport contributes to insulin-stimulated NO synthesis in human endothelial cells, yet attenuation of this is unlikely to underlie the inhibition of insulin-stimulated NO synthesis under high glucose conditions.


Subject(s)
Aorta/drug effects , Arginine/metabolism , Endothelium, Vascular/drug effects , Insulin/pharmacology , Nitric Oxide/biosynthesis , Proto-Oncogene Proteins c-akt/metabolism , Aorta/metabolism , Biological Transport/drug effects , Cell Line , Endothelium, Vascular/metabolism , Humans , Nitric Oxide Synthase Type III/metabolism , Proto-Oncogene Proteins c-akt/genetics
9.
PLoS One ; 6(8): e23248, 2011.
Article in English | MEDLINE | ID: mdl-21858044

ABSTRACT

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 intima-medial 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.


Subject(s)
Carbohydrate Dehydrogenases/genetics , Carotid Intima-Media Thickness , Polymorphism, Single Nucleotide , Adult , Aged , Aged, 80 and over , Amino Acid Sequence , Atherosclerosis/genetics , Family Health , Female , Gene Frequency , Genetic Predisposition to Disease/genetics , Genotype , HEK293 Cells , Humans , Linear Models , Male , Middle Aged , Molecular Sequence Data , Risk Factors , Sequence Homology, Amino Acid , Young Adult
10.
Circ Cardiovasc Genet ; 4(2): 156-62, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21402901

ABSTRACT

BACKGROUND: Polymorphisms in 11-ß hydroxysteroid dehydrogenase type 1 (11ß-HSD1, encoded by HSD11B1) have been reported to be associated with obesity-related cardiovascular risk factors, such as type II diabetes and hypertension. Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular death associated with these factors but has significant additional heritability, the cause of which is undetermined. The 11ß-HSD1 is believed to maintain tonic inhibition of the mineralocorticoid receptor in cardiomyocytes, and mineralocorticoid receptor activation is involved in the pathophysiology of LVH. We assessed the association between polymorphisms in the HSD11B1 gene and left ventricular mass (LVM) in 248 families ascertained through a proband with hypertension. METHODS AND RESULTS: LVM was measured by electrocardiography and echocardiography in 868 and 829 participants, respectively. Single-nucleotide polymorphisms (SNPs) tagging common variation in the HSD11B1 gene were genotyped by mass spectrometry. The rs846910 SNP, which lies in the flanking region 5' to exon 1B of HSD11B1, was associated with LVM both by electrocardiography (≈5% lower LVM per copy of the rare allele, P=0.02) and by echocardiography (≈10% lower LVM per copy of the rare allele, P=0.003). Genotype explained 1% to 2% of the population variability in LVM, or approximately 5% of the heritable fraction. There were no significant associations between any HSD11B1 SNP and blood pressure or body mass index that could have confounded the association with LVM. CONCLUSIONS: Genotype at HSD11B1 has a small, but significant effect on LVM, apparently independently of any effect on obesity-related traits. These findings suggest a novel action of 11ß-HSD1 in the human cardiomyocyte, which may be of therapeutic importance.


Subject(s)
Hypertrophy, Left Ventricular/genetics , 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Blood Pressure/physiology , Body Mass Index , Electrocardiography , Female , Genotype , Humans , Hypertension/complications , Hypertrophy, Left Ventricular/complications , Hypertrophy, Left Ventricular/physiopathology , Male , Mass Spectrometry , Middle Aged , Polymorphism, Single Nucleotide , Receptors, Mineralocorticoid/chemistry , Receptors, Mineralocorticoid/metabolism , Risk Factors
11.
PLoS Genet ; 6(10): e1001177, 2010 Oct 28.
Article in English | MEDLINE | ID: mdl-21082022

ABSTRACT

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5' region of Uromodulin (UMOD; rs13333226, combined P value of 3.6 × 10⁻¹¹). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.


Subject(s)
Blood Pressure , Genome-Wide Association Study/methods , Hypertension/genetics , Uromodulin/genetics , Aged , Alleles , Chromosomes, Human, Pair 16/genetics , Female , Gene Frequency , Genetic Predisposition to Disease , Genome-Wide Association Study/statistics & numerical data , Genotype , Glomerular Filtration Rate , Humans , Hypertension/physiopathology , Linear Models , Male , Meta-Analysis as Topic , Middle Aged , Multivariate Analysis , Polymorphism, Single Nucleotide , Proportional Hazards Models , Risk Factors , Survival Analysis , Uromodulin/blood
12.
J Clin Endocrinol Metab ; 95(11): 5110-21, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20719839

ABSTRACT

CONTEXT: No consensus exists for management of adults with congenital adrenal hyperplasia (CAH) due to a paucity of data from cohorts of meaningful size. OBJECTIVE: Our objective was to establish the health status of adults with CAH. DESIGN AND SETTING: We conducted a prospective cross-sectional study of adults with CAH attending specialized endocrine centers across the United Kingdom. PATIENTS: Participants included 203 CAH patients (199 with 21-hydroxylase deficiency): 138 women, 65 men, median age 34 (range 18-69) years. MAIN OUTCOME MEASURES: Anthropometric, metabolic, and subjective health status was evaluated. Anthropometric measurements were compared with Health Survey for England data, and psychometric data were compared with appropriate reference cohorts. RESULTS: Glucocorticoid treatment consisted of hydrocortisone (26%), prednisolone (43%), dexamethasone (19%), or a combination (10%), with reverse circadian administration in 41% of patients. Control of androgens was highly variable with a normal serum androstenedione found in only 36% of patients, whereas 38% had suppressed levels suggesting glucocorticoid overtreatment. In comparison with Health Survey for England participants, CAH patients were significantly shorter and had a higher body mass index, and women with classic CAH had increased diastolic blood pressure. Metabolic abnormalities were common, including obesity (41%), hypercholesterolemia (46%), insulin resistance (29%), osteopenia (40%), and osteoporosis (7%). Subjective health status was significantly impaired and fertility compromised. CONCLUSIONS: Currently, a minority of adult United Kingdom CAH patients appear to be under endocrine specialist care. In the patients studied, glucocorticoid replacement was generally nonphysiological, and androgen levels were poorly controlled. This was associated with an adverse metabolic profile and impaired fertility and quality of life. Improvements in the clinical management of adults with CAH are required.


Subject(s)
Adrenal Hyperplasia, Congenital/metabolism , Health Status , Hypercholesterolemia/metabolism , Insulin Resistance , Obesity/metabolism , Osteoporosis/metabolism , Adolescent , Adrenal Hyperplasia, Congenital/complications , Adrenal Hyperplasia, Congenital/drug therapy , Adult , Aged , Body Composition , Body Mass Index , Cross-Sectional Studies , Female , Glucocorticoids/therapeutic use , Humans , Hypercholesterolemia/complications , Male , Middle Aged , Obesity/complications , Osteoporosis/complications , Prospective Studies , United Kingdom
13.
Nat Genet ; 42(5): 373-5, 2010 May.
Article in English | MEDLINE | ID: mdl-20383145

ABSTRACT

Using genome-wide association, we identify common variants at 2p12-p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10(-10) to 10(-15)). Of these, rs10206899 (near NAT8, 2p12-p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 x 10(-5) and P = 3.6 x 10(-4), respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease.


Subject(s)
Kidney Failure, Chronic/genetics , Kidney/physiology , Biological Transport , Creatinine/blood , Cystatin C/metabolism , Europe , Gene Expression Regulation , Genetic Markers/genetics , Genetic Predisposition to Disease , Genetic Variation , Genome-Wide Association Study , Genotype , Glomerular Filtration Rate , Humans , Kidney Failure, Chronic/pathology , Models, Genetic
14.
Nature ; 464(7289): 713-20, 2010 Apr 01.
Article in English | MEDLINE | ID: mdl-20360734

ABSTRACT

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.


Subject(s)
DNA Copy Number Variations/genetics , Disease , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study , Arthritis, Rheumatoid/genetics , Case-Control Studies , Crohn Disease/genetics , Diabetes Mellitus/genetics , Gene Frequency/genetics , Humans , Nucleic Acid Hybridization , Oligonucleotide Array Sequence Analysis , Pilot Projects , Polymorphism, Single Nucleotide/genetics , Quality Control
15.
J Am Coll Cardiol ; 55(3): 243-50, 2010 Jan 19.
Article in English | MEDLINE | ID: mdl-20117403

ABSTRACT

OBJECTIVES: This study sought to assess, for the first time, the relationship between serum concentrations of the soluble interleukin-1 receptor family member ST2 (sST2) and serial change in left ventricular (LV) function after acute myocardial infarction (AMI). BACKGROUND: Serum sST2 levels are elevated early after AMI and are associated with lower pre-discharge LV ejection fraction and adverse cardiovascular outcomes. METHODS: The sST2 levels were measured in 100 patients (mean age 58.9 +/- 12.0 years; 77% male), admitted with AMI with resultant LV systolic dysfunction, at baseline and at 12 and 24 weeks. Patients underwent cardiac magnetic resonance imaging and measurement of N-terminal pro-brain natriuretic peptide, norepinephrine, and aldosterone at each time point. RESULTS: Median sST2 decreased from 263.3 pg/ml at baseline to 140.0 pg/ml at 24 weeks (p < 0.001). Serum sST2 correlated significantly with LV ejection fraction at baseline (r = -0.30, p = 0.002) and 24 weeks (r = -0.23, p = 0.026); change in sST2 correlated with change in LV end-diastolic volume index (r = -0.24, p = 0.023). Level of sST2 was positively associated with infarct volume index at baseline (r = 0.26, p = 0.005) and 24 weeks (r = 0.22, p = 0.037), and with change in infarct volume index (r = -0.28, p = 0.001). Level of sST2 was significantly higher in patients with greater infarct transmurality and endocardial extent, and in the presence of microvascular obstruction. Level of sST2 correlated significantly with norepinephrine and aldosterone, but not with N-terminal pro-brain natriuretic peptide. CONCLUSIONS: Measurement of sST2 early after AMI assists in the prediction of medium-term LV functional recovery. Novel relationships were observed between sST2, infarct magnitude/evolution, and aldosterone. Serum sST2 may be of pathophysiological importance in ventricular and infarct remodeling after AMI. (Effects of Eplerenone on Left Ventricular Remodelling Following Heart Attack; NCT00132093).


Subject(s)
Myocardial Infarction/blood , Receptors, Cell Surface/blood , Stroke Volume/physiology , Ventricular Remodeling/physiology , Aged , Biomarkers/blood , Cohort Studies , Double-Blind Method , Eplerenone , Female , Humans , Interleukin-1 Receptor-Like 1 Protein , Male , Middle Aged , Mineralocorticoid Receptor Antagonists/therapeutic use , Myocardial Infarction/drug therapy , Myocardial Infarction/physiopathology , Predictive Value of Tests , Spironolactone/analogs & derivatives , Spironolactone/therapeutic use , Stroke Volume/drug effects , Treatment Outcome , Ventricular Remodeling/drug effects
16.
Biochem J ; 426(1): 85-90, 2010 Jan 27.
Article in English | MEDLINE | ID: mdl-19925457

ABSTRACT

Insulin stimulates endothelial NO (nitric oxide) synthesis via PKB (protein kinase B)/Akt-mediated phosphorylation and activation of eNOS (endothelial NO synthase) at Ser-1177. In previous studies, we have demonstrated that stimulation of eNOS phosphorylation at Ser-1177 may be required, yet is not sufficient for insulin-stimulated NO synthesis. We therefore investigated the role of phosphorylation of eNOS at alternative sites to Ser-1177 as candidate parallel mechanisms contributing to insulin-stimulated NO synthesis. Stimulation of human aortic endothelial cells with insulin rapidly stimulated phosphorylation of both Ser-615 and Ser-1177 on eNOS, whereas phosphorylation of Ser-114, Thr-495 and Ser-633 was unaffected. Insulin-stimulated Ser-615 phosphorylation was abrogated by incubation with the PI3K (phosphoinositide 3-kinase) inhibitor wortmannin, infection with adenoviruses expressing a dominant-negative mutant PKB/Akt or pre-incubation with TNFalpha (tumour necrosis factor alpha), but was unaffected by high culture glucose concentrations. Mutation of Ser-615 to alanine reduced insulin-stimulated NO synthesis, whereas mutation of Ser-615 to aspartic acid increased NO production by NOS in which Ser-1177 had been mutated to an aspartic acid residue. We propose that the rapid PKB-mediated stimulation of phosphorylation of Ser-615 contributes to insulin-stimulated NO synthesis.


Subject(s)
Hypoglycemic Agents/pharmacology , Insulin/pharmacology , Nitric Oxide Synthase Type III/metabolism , Nitric Oxide/biosynthesis , Phosphorylation/drug effects , Serine/metabolism , Blotting, Western , Cells, Cultured , Electrophoresis, Polyacrylamide Gel , HeLa Cells , Humans , Mutagenesis, Site-Directed , Nitric Oxide Synthase Type III/genetics
17.
Hypertension ; 55(2): 567-74, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20038750

ABSTRACT

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.


Subject(s)
Heart Rate/physiology , Hypertension/diagnosis , Hypertension/mortality , Rest , Adult , Age Factors , Analysis of Variance , Antihypertensive Agents/therapeutic use , Blood Pressure Determination , Cohort Studies , Female , Follow-Up Studies , Humans , Hypertension/drug therapy , Male , Middle Aged , Predictive Value of Tests , Probability , Proportional Hazards Models , Registries , Risk Assessment , Severity of Illness Index , Sex Factors , Survival Analysis , Time Factors
18.
Mol Cell Endocrinol ; 300(1-2): 185-91, 2009 Mar 05.
Article in English | MEDLINE | ID: mdl-18848600

ABSTRACT

Aldosterone plays an important role in electrolyte and blood pressure homeostasis. Our studies have focused on the role of aldosterone in essential hypertension. We have shown that plasma aldosterone and ARR are heritable characteristics and that aldosterone concentrations in older subjects are inversely correlated with birthweight and positively correlated with blood pressure. Aldosterone levels are also associated with polymorphic variation in the CYP11B2 gene, which encodes aldosterone synthase, the enzyme responsible for aldosterone production. Interestingly, CYP11B2 polymorphisms are also associated with less efficient activity of 11beta-hydroxylase, encoded by the neighbouring, highly homologous CYP11B1 gene. We propose that a digenic effect leads to increased aldosterone production, with inefficient 11beta-hydroxylation causing a long-term increase in ACTH drive to the adrenal gland and enhanced expression of CYP11B2, thereby resulting in chronically raised aldosterone secretion in response to factors such as angiotensin II and potassium. In susceptible subjects this is likely, over many years, to result in hypertension with relative aldosterone excess.


Subject(s)
Aldosterone/biosynthesis , Hypertension , Blood Pressure/physiology , Cytochrome P-450 CYP11B2/genetics , Cytochrome P-450 CYP11B2/metabolism , Humans , Hypertension/genetics , Hypertension/metabolism , Polymorphism, Genetic , Steroid 11-beta-Hydroxylase/metabolism
19.
J Clin Endocrinol Metab ; 93(10): 3827-32, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18628520

ABSTRACT

CONTEXT: Cortisone reductase deficiency (CRD) is characterized by a failure to regenerate cortisol from cortisone via 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), resulting in increased cortisol clearance, activation of the hypothalamic-pituitary-axis (HPA) and ACTH-mediated adrenal androgen excess. 11beta-HSD1 oxoreductase activity requires the reduced nicotinamide adenine dinucleotide phosphate-generating enzyme hexose-6-phosphate dehydrogenase (H6PDH) within the endoplasmic reticulum. CRD manifests with hyperandrogenism resulting in hirsutism, oligo-amenorrhea, and infertility in females and premature pseudopuberty in males. Recent association studies have failed to corroborate findings that polymorphisms in the genes encoding H6PDH (R453Q) and 11beta-HSD1 (Intron 3 inserted adenine) interact to cause CRD. OBJECTIVE: Our objective was to reevaluate the genetics and steroid biochemistry of patients with CRD. DESIGN: We analyzed 24-h urine collection for steroid biomarkers by gas chromatography/mass spectrometry and sequenced the HSD11B1 and H6PD genes in our CRD cohort. PATIENTS: Patients included four cases presenting with hyperandrogenism and biochemical features clearly indicative of CRD. RESULTS: Gas chromatography/mass spectrometry identified steroid biomarkers that correlated with CRD in each case. Three cases were identified as homozygous (R109AfsX3, Y316X, and G359D) and one case identified as compound heterozygous (c.960G-->A and D620fsX3) for mutations in H6PD. No mutations affecting enzyme activity were identified in the HSD11B1 gene. Expression and activity assays demonstrate loss of function for all reported H6PDH mutations. CONCLUSIONS: CRD is caused by inactivating mutations in the H6PD gene, rendering the 11beta-HSD1 enzyme unable to operate as an oxoreductase, preventing local glucocorticoid regeneration. These data highlight the importance of the redox control of cortisol metabolism and the 11beta-HSD1-H6PDH pathway in regulating hypothalamic-pituitary-adrenal axis activity.


Subject(s)
Biomarkers/analysis , Carbohydrate Dehydrogenases/genetics , Cortisone Reductase/deficiency , DNA Mutational Analysis , Metabolic Diseases/genetics , Adult , Alopecia/complications , Alopecia/genetics , Alopecia/metabolism , Biomarkers/metabolism , Child , Cortisone Reductase/genetics , Female , Hirsutism/complications , Hirsutism/genetics , Hirsutism/metabolism , Humans , Male , Metabolic Diseases/complications , Metabolic Diseases/enzymology , Metabolic Diseases/metabolism , Middle Aged , Models, Biological , Mutation/physiology , Pedigree , Puberty, Precocious/complications , Puberty, Precocious/genetics , Puberty, Precocious/metabolism , Steroids/metabolism
20.
Nephron Clin Pract ; 109(1): c1-8, 2008.
Article in English | MEDLINE | ID: mdl-18463420

ABSTRACT

BACKGROUND: Arterial stiffness is associated with adverse cardiovascular outcomes, particularly in end-stage renal disease (ESRD). One mechanism linking arterial stiffness with cardiovascular events may be the changes in pressure wave reflection on ventricular ejection and coronary perfusion during diastole. We illustrate this using MRI to describe aortic elastic properties and alterations of diastolic flow in comparison to derived central pressure characteristics. METHODS: Ten patients with ESRD and ten control subjects were studied. Transverse images of the ascending aorta were obtained by cardiac MRI. Aortic distensibility was calculated using brachial pulse pressure. MRI flow maps were obtained from the ascending aorta and aortic pressure was calculated using SphygmoCor. RESULTS: ESRD patients had reduced aortic distensibility compared to the controls (median 0.00464 mm Hg(-1) vs. 0.00152 mm Hg(-1), p = 0.0057). Furthermore, in diastole, normal subjects show net reversal of blood flow in the ascending aorta, with a mean of -19.6 versus +7.6 ml/min in the ESRD group; p = 0.045. CONCLUSIONS: Using non-invasive methods we have demonstrated a marked reduction in aortic distensibility along with disturbances in aortic flow, providing insight into the pathophysiology of ventricular-vascular interaction. The normal group showed reversal of diastolic blood flow, which may have a direct relationship with coronary perfusion parameters, which was absent in the ESRD group.


Subject(s)
Aorta/physiopathology , Blood Flow Velocity , Blood Pressure , Image Interpretation, Computer-Assisted/methods , Kidney Failure, Chronic/physiopathology , Magnetic Resonance Imaging/methods , Models, Cardiovascular , Adult , Computer Simulation , Elasticity , Female , Humans , Male , Middle Aged , Stress, Mechanical
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