Phenotypic consequences of variation across the aldosterone synthase and 11‐beta hydroxylase locus in a hypertensive cohort: data from the MRC BRIGHT Study

Freel, E. Marie; Ingram, M; Friel, Elaine C.; Fraser, Robert; Samani, Nilesh J.; Caulfield, Mark; Munroe, Patricia B.; Farrall, Martin; Webster, J; Clayton, David; Dominiczak, Anna F.; Davies, Eleanor; Connell, John

doi:10.1111/j.1365-2265.2007.02971.x

Cited by 26 publications

(19 citation statements)

References 42 publications

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“…These are subtle but significant differences in mRNA levels, which provide a simple putative mechanism to explain the association, reported elsewhere, of Haplotype2 polymorphisms with lower aldosterone levels 7,24 and greater 11β-hydroxylation efficiency. 25,26 These findings are also consistent with the known association between SNPs in the 5′ regulatory region of CYP11B1 and minor impairment of 11β-hydroxylation efficiency 14 ; the relevance of this to the long-term risk of hypertension has been the subject of a detailed review elsewhere. 27 We do not have data on circulating corticosteroid levels in the cohorts studied, and the links among genotype, intermediate biochemical phenotype, and BP still need to be clarified.…”

Section: Discussionsupporting

confidence: 73%

Common Polymorphisms in the CYP11B1 and CYP11B2 Genes: Evidence for a Digenic Influence on Hypertension

et al. 2013

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H ypertension is a highly heritable phenotype, with 50% to 60% of blood pressure (BP) variability being attributable to additive genetic factors. However, the identification of these factors has proved challenging.1,2 The sum of rare and common genetic variants robustly identified through linkage and genomewide association studies (GWAS) explains only 1% to 2% of the population variation in BP and hypertension, and the paucity of signals from large-scale GWAS of BP traits indicates that part of the missing heritability is likely to lie in additional undiscovered common or low frequency variants not currently captured in GWAS single nucleotide polymorphism (SNP) arrays. 3,4 Human and animal data strongly suggest that the locus encompassing the CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) genes could be involved in common forms of hypertension. The locus is causally implicated in rare but important monogenic syndromes associated with cardiovascular dysfunction: aldosterone synthase deficiency leads to salt wasting and hypotension; 11β-hydroxylase deficiency results in mineralocorticoid hypertension as a result of excess deoxycorticosterone production. A chimeric gene comprising the regulatory region of CYP11B1 and the coding region of CYP11B2 is the cause of glucocorticoid-remediable aldosteronism.Abstract-The locus encompassing the corticosteroidogenic genes CYP11B2 and CYP11B1 is of potential importance in essential hypertension. We analyzed the association of polymorphisms at this locus with risk of essential hypertension, using 2 white case-control collections for discovery (n=3340) and confirmation (n=2929). Single-marker and haplotype analyses were performed, with the CYP11B2 Intron 2 Conversion polymorphism showing strongest association with hypertension in both cohorts and in combined analysis (odds ratio=1.16, P=8.54×10). The CYP11B1 ACA haplotype associated with increased risk of hypertension relative to the alternative, GTC (odds ratio=1.11; P=7.4×10), whereas the CYP11B2 TWtC haplotype seemed protective relative to the contrasting CConvT (odds ratio=0.88, P=2.2×10). Analysis spanning the whole CYP11B1/CYP11B2 locus showed that haplotypes associated with raised risk of hypertension tend to coexist. Functional analysis of heterozygous human adrenal tissue demonstrated decreased CYP11B2 expression and increased CYP11B1 expression for those alleles associating with reduced risk of hypertension. These results confirm the hypertensive influence of this locus, with data suggesting a complex digenic mechanism whereby altered relative CYP11B1 and CYP11B2 gene expression could have a chronic effect on enzyme activity and corticosteroid synthesis.

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Section: Discussionsupporting

confidence: 73%

Common Polymorphisms in the CYP11B1 and CYP11B2 Genes: Evidence for a Digenic Influence on Hypertension

et al. 2013

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“…32 Second, in normal subjects, there is a recognized diurnal variation in aldosterone that mirrors that of cortisol, consistent with an effect of ACTH on synthesis of the mineralocorticoid. 33 We have also shown positive correlations between aldosterone and glucocorticoids (and androgens) in a large population-based study, which we suggest is a consequence of shared regulation, 34 and have shown that this might be related to genetic variation at the CYP11B1/B2 locus. 9 Finally, aldosterone regulation is typically maintained as a result of input from multiple trophins, and we proposed previously that the effect of ACTH is to modulate the aldosterone responsiveness to other factors such as angiotensin II and potassium.…”

Section: Discussionmentioning

confidence: 93%

Programming of Hypertension

et al. 2009

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Abstract-Animal models suggest that explanations for the association of low birthweight with adult hypertension may include chronic activation of the hypothalamic-pituitary-adrenal or renin-angiotensin-aldosterone axes. In humans, low birthweight predicts elevated plasma cortisol, but associations with aldosterone have not been reported. We measured aldosterone in serum samples from 205 men and 106 women from 67 to 78 years of age, from Hertfordshire, UK, for whom birthweight was recorded. Participants underwent an overnight low-dose (0.25 mg) dexamethasone suppression test and a low-dose (1 g) ACTH (corticotropin) stimulation test and were genotyped for the -344 C/T polymorphism of the CYP11B2 gene encoding aldosterone synthase. Median aldosterone was 6.22 ng/dL (range 0.15 to 38.74) and was higher in men than women (PϽ0.0001). Higher aldosterone levels after both dexamethasone and ACTH stimulation were associated with higher blood pressure (rϭ0.20, Pϭ0.001; rϭ0.33, PϽ0.0001, respectively) and with lower birthweight (rϭϪ0. 16, Pϭ0.008; rϭϪ0.21, Pϭ0.001, respectively). These associations remained significant after adjusting for age, gender, obesity, and genotype. Our findings supplement previous evidence that aldosterone is an important regulator of blood pressure and suggest that factors in early life that retard fetal growth and program activation of the hypothalamic-pituitary-adrenal axis in humans result not only in higher glucocorticoid activity but also in increased mineralocorticoid activity. Key Words: programming Ⅲ hypertension Ⅲ aldosterone Ⅲ mineralocorticoid Ⅲ glucocorticoid E pidemiological studies have shown that low birthweight, a marker of an adverse intrauterine environment, is associated with development of hypertension in adulthood. 1 One hypothesis to explain this phenomenon is excessive activity of glucocorticoids. 2 Treatment of pregnant rats with dexamethasone reduces birthweight and leads to permanent hypertension and increased hypothalamic-pituitary-adrenal (HPA) axis activity in the offspring. [2][3][4] Similarly, in men and women of low birthweight and with cardiovascular risk factors, including hypertension, we observed increased fasting cortisol, increased excretion of urinary glucocorticoid metabolites, and increased cortisol responses to ACTH stimulation. 5-8 Thus, it has been proposed that elevated glucocorticoid activity resulting from activation of the HPA axis may explain the link between low birthweight and high blood pressure.Chronic activation of the HPA axis may also increase mineralocorticoid activity. This mechanism has been invoked, for example, to explain higher aldosterone levels in subjects with polymorphisms in CYP11B1 and CYP11B2 that associate with lower 11␤-hydroxylase activity, reduced cortisol secretion, and compensatory HPA axis activation. 9 There is substantial evidence implicating mineralocorticoids in the pathogenesis of hypertension. For example, data from the Framingham Offspring Study showed that higher aldosterone levels within the normal range predict...

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“…They were recruited from the local population as part of the control group for the MRC Bright study. 5 Approval for the study was granted by the local Ethics Committees and fully informed written consent from all of the participants was obtained. Anonymized routine patients' samples (n ¼ 266) were used in the ARR method comparison and were from hypertensive patients suspected of suffering from primary or secondary aldosteronism.…”

Section: Patientsmentioning

confidence: 99%

A screening procedure for primary aldosteronism based on the Diasorin Liaison^® automated chemiluminescent immunoassay for direct renin

et al. 2010

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Background: Primary aldosteronism (PA), the most common secondary cause of hypertension, can be screened for using the aldosterone/renin ratio. This ratio is raised in PA and its accuracy depends on the ability to measure plasma renin at extremely low concentrations. Methods: We compared two different procedures for assessing plasma renin. The conventional method, which measures plasma renin activity (PRA), is technically demanding and laborious, and the Diasorin Liaison w method, which measures plasma renin concentration (PRC), is an automated immunoassay. Results from each method were used to calculate the aldosterone/renin ratio (ARR) and the performance of the Diasorin Liaison w method compared with that of the conventional assay using receiver operator characteristic curves. Results: The analytical and functional sensitivity of the PRC method were 2.1 and 5 mIU/mL, respectively. Intra-and interassay precision were ,7.2% and 10.4%, respectively. There was significant (9%) prorenin interference. Samples with PRA . 1.0 ng/mL/h showed significant correlation with PRC (r ¼ 0.93; P , 0.05; n ¼ 146); however, with PRA , 1.0 ng/mL/h, no significant correlation occurred (r ¼ 0.14; P , 0.05; n ¼ 79). An aldosterone ( pmol/L)/PRC(mIU/mL) ratio of .35, in patients with aldosterone .300 pmol/L, resulted in 100% sensitivity and 93% specificity, when compared with the commonly accepted aldosterone ( pmol/L)/PRA (ng/mL/h) ratio of .750, in identifying patients who may suffer from PA. Conclusion: This study indicates the feasibility of using the automated PRC assay as a replacement for the conventional manual PRA assay in calculating the ARR as a first-line screen for PA.

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Phenotypic consequences of variation across the aldosterone synthase and 11‐beta hydroxylase locus in a hypertensive cohort: data from the MRC BRIGHT Study

Cited by 26 publications

References 42 publications

Common Polymorphisms in the CYP11B1 and CYP11B2 Genes: Evidence for a Digenic Influence on Hypertension

Common Polymorphisms in the CYP11B1 and CYP11B2 Genes: Evidence for a Digenic Influence on Hypertension

Programming of Hypertension

A screening procedure for primary aldosteronism based on the Diasorin Liaison^® automated chemiluminescent immunoassay for direct renin

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Phenotypic consequences of variation across the aldosterone synthase and 11‐beta hydroxylase locus in a hypertensive cohort: data from the MRC BRIGHT Study

Cited by 26 publications

References 42 publications

Common Polymorphisms in the CYP11B1 and CYP11B2 Genes: Evidence for a Digenic Influence on Hypertension

Common Polymorphisms in the CYP11B1 and CYP11B2 Genes: Evidence for a Digenic Influence on Hypertension

Programming of Hypertension

A screening procedure for primary aldosteronism based on the Diasorin Liaison® automated chemiluminescent immunoassay for direct renin

Contact Info

Product

Resources

About

A screening procedure for primary aldosteronism based on the Diasorin Liaison^® automated chemiluminescent immunoassay for direct renin