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      Effect of variation in CYP11B1 and CYP11B2 on corticosteroid phenotype and hypothalamic–pituitary–adrenal axis activity in hypertensive and normotensive subjects

      , , ,   , , ,
      Clinical Endocrinology
      Wiley

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          Abstract

          Aldosterone is important in the development of hypertension. We have shown that a single nucleotide polymorphism (SNP) (-344T) in the 5' regulatory region (UTR) of the gene encoding aldosterone synthase (CYP11B2) associates with aldosterone excess and hypertension as well as altered adrenal 11-hydroxylation efficiency (deoxycortisol to cortisol). This conversion is carried out by the enzyme 11beta-hydroxylase, encoded by the adjacent gene, CYP11B1. We proposed that the effects of CYP11B2 are explained by linkage disequilibrium (LD) across the CYP11B locus. We have demonstrated high LD across this locus and identified two SNPs in the 5' UTR of CYP11B1 (-1859 G/T, -1889 A/G) that associate with reduced transcription in vitro and altered 11-hydroxylation efficiency in vivo. Accordingly, we hypothesized that the reduced adrenal 11-hydroxylation may lead to chronic resetting of the pituitary-adrenal axis, with chronically increased ACTH drive resulting in aldosterone excess. To test this, we examined hypothalamic-pituitary-adrenal (HPA) axis activity in hypertensive and normotensive individuals stratified according to genotype at CYP11B2 (-344T/C) and CYP11B1 (-1859 G/T, -1889 A/G). Fifty-six subjects homozygous for CYP11B2 SNP (27 TT, 12 CC), and 38 homozygous for CYP11B1 SNPs (18 TTGG, 20 GGAA) were recruited. Diurnal variation and the effects of dexamethasone suppression and ACTH stimulation on plasma aldosterone, cortisol and ACTH under controlled conditions were studied. Subjects with SNPs associated with reduced 11-hydroxylation efficiency (-344T CYP11B2; TTGG CYP11B1) showed reduced inhibition of ACTH after dexamethasone (P = 0.05) and an altered cortisol-ACTH relationship (decreased cortisol-ACTH ratio, P < 0.02). The same individuals also demonstrated close correlations between plasma cortisol and aldosterone (-344T CYP11B2 r = 0.508, P < 0.004; TTGG CYP11B1 r = 0.563, P < 0.003) suggesting that there was common regulation (possibly ACTH) of these hormones in genetically susceptible subjects. Variation in CYP11B2 and CYP11B1 associates with chronic up-regulation of the HPA axis. These novel data support the suggestion that chronic aldosterone excess, in genetically susceptible individuals, may be a consequence of increased ACTH drive to the adrenal and identify novel molecular mechanisms that may lead to the development of hypertension within the general population.

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          Most cited references22

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          Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents.

          Primary aldosteronism (PA) is a common form of endocrine hypertension previously believed to account for less than 1% of hypertensive patients. Hypokalemia was considered a prerequisite for pursuing diagnostic tests for PA. Recent studies applying the plasma aldosterone/plasma renin activity ratio (ARR) as a screening test have reported a higher prevalence. This study is a retrospective evaluation of the diagnosis of PA from clinical centers in five continents before and after the widespread use of the ARR as a screening test. The application of this strategy to a greater number of hypertensives led to a 5- to 15-fold increase in the identification of patients affected by PA. Only a small proportion of patients (between 9 and 37%) were hypokalemic. The annual detection rate of aldosterone-producing adenoma (APA) increased in all centers (by 1.3-6.3 times) after the wide application of ARR. Aldosterone-producing adenomas constituted a much higher proportion of patients with PA in the four centers that employed adrenal venous sampling (28-50%) than in the center that did not (9%). In conclusion, the wide use of the ARR as a screening test in hypertensive patients led to a marked increase in the detection rate of PA.
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            High incidence of primary aldosteronism in 199 patients referred with hypertension.

            1. This study sought to assess the incidence of primary aldosteronism in 199 hypertensives who were normokalaemic and in whom the question of primary aldosteronism had never been raised. 2. The screening test applied was the aldosterone to renin ratio in plasma, which was raised in 40 and normal in 159 patients. A second ratio was normal in 14 of these 40. 3. Twenty-two patients with two further raised ratios required fludrocortisone suppression testing. This has been completed in 17, and failure to suppress led to a diagnosis of primary aldosteronism in all. 4. A dexamethasone suppression test (DST) excluded ACTH-dependent hyperaldosteronism and laterality of aldosterone production was determined by adrenal vein sampling. 5. Unilaterality in five patients led to adrenalectomy in four and spironolactone in one. Bilaterality in six patients led to spironolactone. 6. This study so far provides a proven (minimum) incidence for primary aldosteronism of 8.5%, a probable incidence of 12.0% (including two raised ratios) and a possible (maximum) incidence of 13.0% (leaving out those with second ratio normal). Exclusion of hypokalaemic hypertensives will lead to an underestimation of the true incidence of primary aldosteronism. 7. Based on this and other evidence, it is estimated that the incidence of primary aldosteronism in the 'essential hypertensive' population is between 5 and 15%, and is probably around 10%.
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              High plasma aldosterone levels on admission are associated with death in patients presenting with acute ST-elevation myocardial infarction.

              Aldosterone, the final mediator of the renin-angiotensin-aldosterone pathway, is at its highest plasma levels at presentation for ST-elevation myocardial infarction (STEMI). Whether aldosterone level at presentation for STEMI is associated with adverse outcome remains unknown. Plasma aldosterone levels were measured at presentation in consecutive patients referred for primary percutaneous coronary intervention for STEMI. We assessed the association between aldosterone levels and in-hospital events and mortality during a 6-month follow-up. Of 356 STEMI patients, 23 and 36 died during the hospital stay and 6-month follow-up period, respectively. Nine other patients survived in-hospital cardiac arrest. High aldosterone levels were associated with an almost stepwise increase in rates of in-hospital death (P=0.01), cardiovascular death (P=0.03), heart failure (P=0.005), ventricular fibrillation (P=0.02), and resuscitated cardiac arrest (P=0.01). After adjustment for age, Killip class, and reperfusion status, compared with patients in the first aldosterone quartile group, those in the highest quartile were at higher risk of death (hazard ratio 3.28, 95% CI 1.09 to 9.89, P=0.035) and death or resuscitated cardiac arrest (hazard ratio 3.74, 95% CI 1.40 to 9.98, P=0.008) during the follow-up. Plasma aldosterone levels on admission among patients referred for primary percutaneous coronary intervention for STEMI are associated with early and late adverse clinical outcomes, including mortality. The association between high aldosterone levels and late mortality is independent of age, heart failure, and reperfusion status. Such results underline the pivotal role of aldosterone and justify a randomized trial to assess the early administration of aldosterone antagonists in the setting of STEMI.
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                Author and article information

                Journal
                Clinical Endocrinology
                Clin Endocrinol
                Wiley
                0300-0664
                1365-2265
                May 2008
                May 2008
                : 68
                : 5
                : 700-706
                Article
                10.1111/j.1365-2265.2007.03116.x
                17980006
                b47049bd-c4ee-4ac3-a622-23ad51f556de
                © 2008

                http://doi.wiley.com/10.1002/tdm_license_1.1

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