The chimeric gene linked to glucocorticoid-suppressible hyperaldosteronism encodes a fused P-450 protein possessing aldosterone synthase activity.

Glucocorticoid-suppressible hyperaldosteronism (GSH) is one variety of primary aldosteronism with hypertension and is inherited in an autosomal dominant mode. A recent report has indicated that GSH is caused by a gene duplication arising from unequal crossing over between the two genes, CYP11B1 and CYP11B2, encoding P-450(11 beta) and P-450C18, respectively (Lifton et al. Nature (1992) 355, 262-265). The nucleotide sequence analysis in the present study has demonstrated that unequal crossing over in the chimeric gene formed by the gene duplication occurs within the region from the 3'-portion of exon 4 through the 5'-portion of intron 4 in Australian GSH patients. Namely, the chimeric gene encodes a fused P-450 protein consisting of the amino-terminal side of P-450(11 beta) (encoded by exons 1-4 of CYP11B1) and the carboxyl-terminal side of P-450C18 (encoded by exons 5-9 of CYP11B2). When a cDNA corresponding to the chimeric gene is transfected into COS-7 cells, the fused P-450 protein expressed in the mitochondria exhibits steroid 18-hydroxylase or aldosterone synthase activity. These results provide the molecular genetic basis for the characteristic biochemical phenotype of GSH patients.     

Familial hyperaldosteronism

Primary aldosteronism (PAL) may be as much as ten times more common than has been traditionally thought, with most patients normokalemic. The study of familial varieties has facilitated a fuller appreciation of the nature and diversity of its clinical, biochemical, morphological and molecular aspects. In familial hyperaldosteronism type I (FH-I), glucocorticoid-remediable PAL is caused by inheritance of an ACTH-regulated, hybrid CYP11B1/CYP11B2 gene. Genetic testing has greatly facilitated diagnosis. Hypertension severity varies widely, demonstrating relationships with gender, affected parent's gender, urinary kallikrein level, degree of biochemical disturbance and hybrid gene crossover point position. Analyses of aldosterone/PRA/cortisol 'day-curves' have revealed that (1) the hybrid gene dominates over wild type CYP11B2 in terms of aldosterone regulation and (2) correction of hypertension in FH-I requires only partial suppression of ACTH, and much smaller glucocorticoid doses than those previously recommended. Familial hyperaldosteronism type II is not glucocorticoid-remediable, and is clinically, biochemically and morphologically indistinguishable from apparently sporadic PAL. In one informative family available for linkage analysis, FH-II does not segregate with either the CYP11B2, AT1 or MEN1 genes, but a genome-wide search has revealed linkage with a locus in chromosome 7. As has already occurred in FH-I, elucidation of causative mutations is likely to facilitate earlier detection of PAL and other curable or specifically treatable forms of hypertension.     

Can primary hyperaldosteronism be considered as a specific form of diabetes mellitus?

Aldosterone-producing adenoma (aldosteronoma)--the most frequent form of primary hyperaldosteronism (PH)--is considered a specific form of diabetes mellitus (DM). In a previous study we demonstrated insulin resistance in patients with PH. We have therefore undertaken a study to evaluate the incidence of abnormalities of glucose metabolism in patients with PH (36 subjects) compared to control subjects with essential hypertension (EH) (21 patients). The following parameters were measured in all studied subjects: office blood pressure (by mercury sphygmomanometer in the sitting position), body mass index (BMI), plasma potassium, plasma glucose and insulin levels during oral glucose tolerance test (OGTT) (0, 60, 120 min), plasma renin activity and plasma aldosterone. Although patients with PH tended to have higher stimulated plasma glucose levels after 60 and 120 min compared to EH, these differences did not attain statistical significance. Patients with EH tended to have higher insulin levels at each measured interval, but due to a high variability these differences were again not significant. There were no significant differences between PH and EH in the proportion of diabetics (20% vs. 14%) or patients with impaired glucose tolerance (18% vs. 10%). In conclusion, we have found the absence of significant differences in the frequency of diabetes mellitus, impaired glucose tolerance and insulin resistance in patients with EH and PH. Our data thus do not support the idea of primary hyperaldosteronism as a specific type of diabetes mellitus. Furthermore, our results indicate that glucose metabolic characteristics in essential hypertension and primary hyperaldosteronism tend to be similar. The definitive conclusion with respect to the possible causal relationship between DM and PH, however, can be obtained only on larger groups of subjects, in particular after the evaluation of the effect of surgical/pharmacological treatment of primary hyperaldosteronism.     

Aldosterone synthase cytochrome P-450 expressed in the adrenals of patients with primary aldosteronism

A human cytochrome P-450 with aldosterone synthase activity was purified from the mitochondria of an aldosterone-producing adenoma. It was recognized by an anti-bovine cytochrome P-450(11 beta) IgG and by a specific antibody raised against a portion of the CYP11B2 gene product, one of the two putative proteins encoded by human cytochrome P-450(11 beta)-related genes (Mornet, E., Dupont, J., Vitek, A., and White, P. C. (1989) J. Biol. Chem. 264, 20961-20967). A similar and probably the same aldosterone synthase cytochrome P-450 was detected in the adrenal of a patient with idiopathic hyperaldosteronism. These aldosterone synthases were distinguishable from cytochrome P-450(11 beta), the product of another cytochrome P-450(11 beta)-related gene, i.e. CYP11B1, by their catalytic, molecular, and immunological properties and also by their localization. The latter enzyme was unable to produce aldosterone and did not react with the specific antibody against the CYP11B2 gene product. It was present both in tumor and non-tumor portions of the adrenals carrying the adenoma and in normal adrenal cortex. On the other hand, aldosterone synthase cytochrome P-450 localized in the tumor portions of the adrenals or in the adrenal of a patient with idiopathic hyperaldosteronism. Thus aldosterone synthase cytochrome P-450, a distinct species from cytochrome P-450(11 beta), is responsible for the biosynthesis of aldosterone in the human, at least in patients suffering from primary aldosteronism.     

Two distinct areas of unequal crossingover within the steroid 21-hydroxylase genes produce absence of CYP21B

We mapped crossover sites in chimeric, recombinant CYP21 genes from six patients with salt-losing congenital adrenal hyperplasia (CAH). Nucleotide sequences unique to the CYP21A pseudogene or to the active CYP21B gene were mapped using gene-specific restriction sites and oligonucleotide hybridizations. Each chimeric CYP21 gene in the CYP21-deletion linked haplotypes contained sequences near the 5' end that were characteristic of CYP21A and only a single transition from sequences of CYP21A to those of CYP21B at the 3' end. The transitions all occurred within either of two discrete regions (+470 to +999 and +1375 to +1993). All eight chimeric CYP21 genes coupled with HLA-Bw47 in five unrelated patients had the CYP21A-CYP21B sequence transition within the same gene region (+1375 to +1993). One of the three other "CYP21B deletion" haplotypes (HLA-B7) had a sequence transition within this same region, while in the other two haplotypes (HLA-B61 and HLA-B18) the transition occurred between base pairs +470 and +999. By contrast, both CYP21 genes in a haplotype containing a gene conversion of CYP21B to CYP21A contained apparent transitions between sequences of CYP21A and CYP21B. We conclude that a single, unequal crossingover between the CYP21A and the CYP21B genes yields deletion of the active CYP21 gene and salt-losing CAH and that these crossingovers do not occur randomly within the CYP21 genes of our patients.     

Comparative genetic analysis of different forms of low-renin arterial hypertension

High level of clinical and genetic heterogeneity is a characteristic of arterial hypertension (AH) that is one of the most wide-spread cardiovascular diseases. In most cases (excluding a few monogenic forms), AH is a polygenic disease and genes of renin-angiotensin-aldosterone system play an important role in AH predisposition. 20-25% AH cases occur during low activity of renin in blood plasma (low-renin form of AH) while aldosterone production can be increased (hyperaldosteronism, HA) or normal. We examined polymorphism of genes that code the renin-angiotensin-aldosterone system components in the groups of low-renin forms of AH, namely, primary HA, idiopathic HA and AH with normal level of aldosterone. For all HA cases, the absence of chimeric CYP11B2/CYP11B1 gene that is a cause for monogenic disease--amilial HA of first type, was shown. A comparison of distributions of alleles and genotypes of polymorphous regions of genes: CYP11B2 (C-344T), REN (C-5434T, C-5312T and A BglI G), AGT (Thr174Met), ACE (I/D), CMA (G-1903A), AT2R1 (A1166C) and of their combinations is the groups described above was done. The analysis of carriership of the alleles and genotypes combinations of the polymorphous regions has shown that genes CYP11B2, REN, ACE, CMA andA T2R1 participate in development of low-renin HA. The results are evidence of similarities and some definite differences in genetic nature of the different forms of low-renin AH and, to say more widely, argue that the investigation of genetic predisposition for clinically heterogeneous forms of polygene diseases by comparison of groups of patients, separated in accordance with peculiarities of disease course, holds much promise for their hereditary background understanding.     

New aspects on primary aldosteronism

The adrenal cortex synthesizes and releases steroid hormones, mainly mineralocorticoids and glucocorticoids. There is a functional zonation of the adrenal cortex and steroid synthesis is thoroughly regulated. Overproduction of aldosterone, primary aldosteronism, may be much more common than previously known and may be responsible for 10% of essential hypertension. Primary aldosteronism is characterized by autonomous production of aldosterone, suppressed renin activity, hypokalemia, and hypertension. The two most common forms are unilateral adenoma and bilateral hyperplasia. In spite of thorough clinical workup and careful histopathology it is often difficult to differentiate between adenoma and hyperplasia. The gene CYP11B2 encodes the steroid synthesizing enzymes for aldosterone production, while the genes CYP17 and CYP11B1 are needed for cortisol production. Most normal controls show expression of CYP11B2 in zona glomerulosa. Expression of CYP11B1 and CYP17 is seen in zona fasciculata and reticularis, whereas the expression of CYP21 is present in all three cortical layers. Adenomas from patients with primary aldosteronism show considerable variation in the expression of CYP11B2. Adenomas from patients with Cushing's syndrome have a strong expression of CYP11B1 and CYP17. In a patient material of 29 cases of primary aldosteronism, 4 patients had small nodules detected with expression of CYP11B2 gene. These nodules were not visualized on CT, whereas adrenal masses seen on CT in these patients showed CYP11B1 and CYP17 gene expression. This suggests that these small nodules are responsible for the aldosterone production and this is characteristic of nodular hyperplasia in patients with primary aldosteronism. In conclusion, this method to visualize mRNA gene expression of steroidogenic enzymes, and especially expression of CYP11B2, has increased the knowledge of adrenal pathophysiology. The results emphasize the value to include functional studies (venous sampling and/or scintigraphy) in the preoperative work up of patients with primary aldosteronism.     

Comparative genetic analysis of different forms of low-renin arterial hypertension

Arterial hypertension (AH) ranks among the most widespread cardiovascular diseases and is clinically and genetically heterogeneous. Except for rare monogenic forms, AH is polygenic, and an important role in AH predisposition belongs to genes of the renin-angiotensin-aldosterone system. Low renin activity in blood plasma is observed in 20–25% of AH cases (low-renin form of AH), while aldosterone production can be elevated (hyperaldosteronism, HA) or normal in these cases. Several polymorphisms of the genes coding for the renin-angiotensin-aldosterone system components were studied in patients with low-renin AH forms: primary HA, idiopathic HA, and AH with a normal aldosterone level. The chimeric CYP11B2/CYP11B1 gene, causing monogenic familial HA type 1, was absent from all HA cases studied. The patient groups were compared with respect to the allele and genotype frequency distributions of the polymorphisms of several genes (CYP11B2 (C-344T), REN (C-5434T, C-5312T, and A BglI G), AGT (Thr174Met), ACE (I/D), CMA (G-1903A), AT2R1 (A1166C)), and their combinations. Analysis of the carriership of the allele and genotype combinations implicated CYP11B2, REN, ACE, CMA, and AT2R1 in low-renin HA. The results revealed both similar and different features in the genetic nature of different low-renin AH forms. Investigation of the genetic predisposition to clinically heterogeneous forms of polygenic diseases by comparing patient groups, formed in accordance with peculiarities of the disease course, holds much promise for understanding their hereditary background.     

Disorders of the aldosterone synthase and steroid 11beta-hydroxylase deficiencies

The most potent corticosteroids are 11beta-hydroxylated compounds. In humans, two cytochrome P450 isoenzymes with 11beta-hydroxylase activity, catalysing the biosynthesis of cortisol and aldosterone, are present in the adrenal cortex. CYP11B1, the gene encoding 11beta-hydroxylase (P450c11), is expressed on high levels in the zona fasciculata and is regulated by ACTH. CYP11B2, the gene encoding aldosterone synthase (P450c11Aldo), is expressed in the zona glomerulosa under primary control of the renin-angiotensin system. Aldosterone synthase has 11beta-hydroxylase activity as well as 18-hydroxylase activity and 18-oxidase activity. The substrate for CYP11B2 is 11-deoxycorticosterone, that of CYP11B1 is 11-deoxycortisol. Mutations in CYP11B1 cause congenital adrenal hyperplasia (CAH) due to 11beta-hydroxylase deficiency. This disorder is characterized by androgen excess and hypertension. Mutations in CYP11B2 cause congenital hypoaldosteronism (aldosterone synthase deficiency) which is characterized by life-threatening salt loss, failure to thrive, hyponatraemia and hyperkalaemia in early infancy. Both disorders have an autosomal recessive inheritance. Classical and nonclassical forms of 11beta-hydroxylase deficiency can be distinguished. Studies in heterozygotes for classical 11beta-hydroxylase deficiency show inconsistent results with no or only mild hormonal abnormalities (elevated plasma levels of 11-deoxycortisol after ACTH stimulation). In infants with congenital hypoaldosteronism, a comparable frequency of 18-hydroxylase deficiency (aldosterone synthase deficiency type I) and of 18-oxidase deficiency (aldosterone synthase deficiency type II) can be found. Molecular genetic studies of the CYP11B1 and CYP11B2 genes in 11beta-hydroxylase deficiency or aldosterone synthase deficiency have led to the identification of several mutations. Transfection experiments showed loss of enzyme activity in vitro. In some of the patients with 18-oxidase deficiency (aldosterone synthase deficiency type II) no mutations in the CYP11B2 gene were identified. Refined methods for steroid determination are the basis for the diagnosis of inborn errors of steroidogenesis. Molecular genetic studies are complementary; on the one hand, they have practical importance for the prenatal diagnosis of virilizing CAH forms and on the other hand, they are of theoretical importance in terms of our understanding of the functioning of cytochrome P450 enzymes. Copyrightz1999S.KargerAG, Basel     

Association of the K173R variant and haplotypes in the aldosterone synthase gene with essential hypertension

Aldosterone synthase plays an important role in determining the levels of aldosterone secretion. Polymorphisms of the aldosterone synthase gene (CYP11B2) are suggested to be associated with essential hypertension. In this study, we examined associations of CYP11B2 polymorphisms [?344T/C, K173R and intron 2 conversion (IC)] with Korean hypertensive patients. Three hundred and forty patients with hypertension and 515 healthy normotensive subjects were studied. CYP11B2 polymorphisms in the subjects were analyzed by polymerase chain reaction–restriction fragment length polymorphism techniques. Of the three polymorphisms studied, we observed a significant difference in the mutant genotype of K173R polymorphism between the hypertensive and normotensive groups (P = 0.03). Several haplotype frequencies composed of three polymorphisms were also associated with hypertension susceptibility. Association between the K173R polymorphism and values of BMI, HDL-cholesterol and WC was found in the hypertensive group. However, no associations of ?344T/C and IC polymorphisms were found with the risk of hypertension and clinical parameters. Based on these results, the K173R variant and haplotypes of the CYP11B2 gene might affect hypertension susceptibility.     

Familial Hyperaldosteronism Type 3 with a Rapidly Growing Adrenal Tumor: An In Situ Aldosterone Imaging Study

Primary aldosteronism is most often caused by aldosterone-producing adenoma (APA) and bi-lateral adrenal hyperplasia. Most APAs are caused by somatic mutations of various ion channels and pumps, the most common being the inward-rectifying potassium channel KCNJ5. Germ line mutations of KCNJ5 cause familial hyperaldosteronism type 3 (FH3), which is associated with severe hyperaldosteronism and hypertension. We present an unusual case of FH3 in a young woman, first diagnosed with primary aldosteronism at the age of 6 years, with bilateral adrenal hyperplasia, who underwent unilateral adrenalectomy (left adrenal) to alleviate hyperaldosteronism. However, her hyperaldosteronism persisted. At the age of 26 years, tomography of the remaining adrenal revealed two different adrenal tumors, one of which grew substantially in 4 months; therefore, the adrenal gland was removed. A comprehensive histological, immunohistochemical, and molecular evaluation of various sections of the adrenal gland and in situ visualization of aldosterone, using matrix-assisted laser desorption/ionization imaging mass spectrometry, was performed. Aldosterone synthase (CYP11B2) immunoreactivity was observed in the tumors and adrenal gland. The larger tumor also harbored a somatic β-catenin activating mutation. Aldosterone visualized in situ was only found in the subcapsular regions of the adrenal and not in the tumors. Collectively, this case of FH3 presented unusual tumor development and histological/molecular findings.     

Development of a test system for inhibitors of human aldosterone synthase (CYP11B2): screening in fission yeast and evaluation of selectivity in V79 cells

Aldosterone synthase (CYP11B2) is a mitochondrial cytochrome P450 enzyme catalyzing the last steps of aldosterone production in the adrenal cortex. A new pharmacological approach for the treatment of the aldosterone induced effects in congestive heart failure and all forms of hyperaldosteronism could be the use of CYP11B2 inhibitors. In search for such compounds, it was our goal to develop a cellular enzyme assay suitable for screening high numbers of compounds. An assay procedure for the evaluation of inhibitors using the human CYP11B2 expressed in fission yeast Schizosaccharomyces pombe was established and a series of 10 compounds was tested in this whole cellular system. Human 11beta-hydroxylase (CYP11B1), which catalyzes the production of glucocorticoids, shows more than 90% homology compared to human CYP11B2. As this enzyme should not be affected, strong inhibitors of CYP11B2 have to be tested for selectivity. For that purpose, an assay procedure with V79MZ cells that express human CYP11B1 and CYP11B2, respectively, was integrated into the evaluation process. Using these screening procedures a potent and rather selective non-steroidal inhibitor of human CYP11B2 was detected with an IC(50) value of 59nM. We also identified a very potent inhibitor of both enzymes showing a stronger inhibitory activity against the cortisol producing CYP11B1.     

Biochemical markers of endothelial dysfunction in patients with endocrine and essential hypertension

The aim of our study was to evaluate potential differences in the concentration of biochemical markers of endothelial dysfunction between essential hypertension, endocrine hypertension (pheochromocytoma, primary hyperaldosteronism) and control healthy group and to assess a potential relationship between these markers of endothelial dysfunction and vasopressor substances overproduced in endocrine hypertension. We have investigated 21 patients with moderate essential hypertension, 29 patients with primary hyperaldosteronism, 24 subjects with pheochromocytoma and 26 healthy volunteers. Following parameters of endothelial dysfunction were measured, von Willebrand factor (vWf), plasminogen activator (t-PA) and E-selectin (E-sel). Clinical blood pressure was measured according to the European Society of Hypertension recommendations. We found significantly higher levels of the von Willebrand factor in patients with essential hypertension in comparison with a control group (114+/-20 IU/dl vs 90+/-47 IU/dl; P=0.04) and patients with primary hyperaldosteronism (114+/-20 IU/dl vs 99+/-11 IU/dl; P=0.01). Patients with endocrine hypertension revealed increased levels of vWF compared to the control group, but these differences did not reach statistical significance. Levels of t-PA were increased in patients with pheochromocytoma in comparison with the control group (4.6+/-1.9 ng/ml vs 3.4+/-0.9 ng/ml; P=0.01) and with primary hyperaldosteronism (4.6+/-1.9 ng/ml vs 3.4+/-1.1 ng/ml; P<0.01). In case of E-selectin we found lower levels in patients with pheochromocytoma in comparison with other groups, but they differed significantly only with primary hyperaldosteronism (40.2+/-15.0 ng/ml vs 51.3+/-23.0 ng/ml; P=0.05). Our study did not reveal any convincing evidence of differences in the levels of biochemical markers of endothelial dysfunction between essential and endocrine hypertension. No correlation between the biochemical markers of endothelial dysfunction and vasopressor substances activated in endocrine hypertension was found.     

Contribution of cytochrome P450 1B1 to hypertension and associated pathophysiology: a novel target for antihypertensive agents

The aim of this review is to discuss the contribution of cytochrome P450 (CYP) 1B1 in vascular smooth muscle cell growth, hypertension, and associated pathophysiology. CYP1B1 is expressed in cardiovascular and renal tissues, and mediates angiotensin II (Ang II)-induced activation of NADPH oxidase and generation of reactive oxygen species (ROS), and vascular smooth muscle cell migration, proliferation, and hypertrophy. Moreover, CYP1B1 contributes to the development and/or maintenance of hypertension produced by Ang II-, deoxycorticosterone (DOCA)-salt-, and N(ω)-nitro-L-arginine methyl ester-induced hypertension and in spontaneously hypertensive rats. The pathophysiological changes, including cardiovascular hypertrophy, increased vascular reactivity, endothelial and renal dysfunction, injury and inflammation associated with Ang II- and/or DOCA-salt induced hypertension in rats, and Ang II-induced hypertension in mice are minimized by inhibition of CYP1B1 activity with 2,4,3',5'-tetramethoxystilbene or by Cyp1b1 gene disruption in mice. These pathophysiological changes appear to be mediated by increased production of ROS via CYP1B1-dependent NADPH oxidase activity and extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and c-Src.     

A new locus on chromosome 12p13.3 for pseudohypoaldosteronism type II, an autosomal dominant form of hypertension

Pseudohypoaldosteronism type II (PHA2) is a rare autosomal dominant form of volume-dependent low-renin hypertension characterized by hyperkalemia and hyperchloremic acidosis but also by a normal glomerular filtration rate. These features, together with the correction of blood pressure and metabolic abnormalities by small doses of thiazide diuretics, suggest a primary renal tubular defect. Two loci have previously been mapped at low resolution to chromosome 1q31-42 (PHA2A) and 17p11-q21 (PHA2B). We have now analyzed a new, large French pedigree, in which 12 affected members over three generations confirmed the autosomal dominant inheritance. Affected subjects had hypertension together with long-term hyperkalemia (range 5.2-6.2 mmol/liter), hyperchloremia (range: 100-109 mmol/liter), normal plasma creatinine (range: 63-129 mmol/liter) and low renin levels. Genetic linkage was excluded for both PHA2A and PHA2B loci (all LOD scores Z<-3.2 at recombination fraction [theta] 0), as well as for the thiazide-sensitive sodium-chloride cotransporter gene. A genome-wide scan using 383 microsatellite markers showed a strong linkage with the chromosome 12p13 region (maximum LOD score Z=6.18, straight theta=0, at D12S99). Haplotype analysis using 10 additional polymorphic markers led to a minimum 13-cM interval flanked by D12S1652 and D12S336, thus defining a new PHA2C locus. Analysis of two obvious candidate genes (SCNN1A and GNb3) located within the interval showed no deleterious mutation. In conclusion, we hereby demonstrate further genetic heterogeneity of this Mendelian form of hypertension and identify a new PHA2C locus, the most compelling and precise linkage interval described to date.     

Impaired insulin action in primary hyperaldosteronism

The presence of insulin resistance is frequently found in essential hypertension. There are, however, only sparse data with respect to the potential presence of insulin resistance in patients with secondary hypertension. We have therefore undertaken a study to reveal the potential occurrence of insulin resistance in primary hyperaldosteronism (PH). The hyperinsulinemic euglycemic clamp technique together with the evaluation of insulin receptor characteristics were used to study insulin resistance in 12 patients with PH. The measured parameters were compared to normal values in control subjects. We have found a significantly lower glucose disposal rate (M, micromol/kg/min) (18.7+/-6 vs. 29.3+/-4), decreased tissue insulin sensitivity index (M/I, micromol/kg/min per mU/l x100) (23.7+/-9.8 vs. 37.5+/-11.6) and also lower metabolic clearance rate of glucose (MCRg, ml/kg/min) (3.8+/-1.5 vs. 7.0+/-1.1) in patients with primary hyperaldosteronism. The insulin receptor characteristics on erythrocytes did not differ in primary hyperaldosteronism as compared to control healthy subjects. We thus conclude that insulin resistance is also present in secondary forms of hypertension (primary hyperaldosteronism) which indicates the heterogeneity of impaired insulin action in patients with arterial hypertension.     

Haplotype-Based Case?CControl Study of the Human CYP11B2 Gene and Essential Hypertension in Yi and Hani Minorities of China

This haplotype-based case-control study investigated whether the aldosterone synthase gene (CYP11B2) might be implicated in the pathogenesis of essential hypertension in Yi (226 individuals) and Hani (296 individuals) minorities of China. Four tag SNPs (rs4536, rs4545, rs3097, and rs3802230) and the K173R polymorphism were genotyped using the PCR-RFLP method. In the Hani minority, rs4536 was significantly associated with hypertension, after Bonferroni correction. H9 AGGC constructed by tag SNPs was significantly higher in hypertensives than in controls (P?=?0.001). Further, we observed that haplotype AGGC remained significantly associated with male hypertension after adjustment for covariates (OR?=?3.76, P?=?0.002). In the Yi minority, it was found that the CYP11B2 gene was not significantly associated with hypertension. These results indicated that haplotype AGGC conferred an increased risk for hypertension in the Hani minority male. In addition, CYP11B2 may not be associated with hypertension in the Yi minority of China.