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(Hypertension. 1996;28:478-482.)
© 1996 American Heart Association, Inc.

Articles

Genetic Association of 11ß-Hydroxysteroid Dehydrogenase Type 2 (HSD11B2) Flanking Microsatellites With Essential Hypertension in Blacks

Bracie Watson, Jr; Suzanne M. Bergman; Angela Myracle; David F. Callen; Ronald T. Acton; David G. Warnock

the Division of Nephrology, University of Alabama School of Medicine, Nephrology Research and Training Center, and Department of Veterans Affairs Medical Center, Birmingham, Ala (B.W., S.M.B., A.M., D.G.W.); Department of Cytogenetics and Molecular Genetics, Women's and Children's Hospital, North Adelaide, South Australia (D.F.C.); and Departments of Microbiology, Medicine and the Immunogenetics/DNA Diagnostic Laboratory–University of Alabama Health Services Foundation, Birmingham (R.T.A.).

Correspondence to Bracie Watson, Jr, PhD, Division of Nephrology, Department of Medicine, Nephrology Research and Training Center, University of Alabama at Birmingham, Zeigler Research Building, 703 S 19th St, Birmingham, AL 35294-0007. E-mail bracie_watson.nephrology@nrtc.dom.uab.edu.

	Abstract

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11ß-Hydroxysteroid dehydrogenase type 2 (11ß-HSD2) specifically modulates access of the mineralocorticoid aldosterone to the kidney mineralocorticoid type 1 receptors in a physiological environment in which there is a molar excess of cortisol. Cortisol and aldosterone have similar affinities for mineralocorticoid receptors. Mechanistically, 11ß-HSD2 converts cortisol to cortisone. The other known isoform, 11ß-HSD1, not only catalyzes the cortisol to cortisone reaction but also the reverse reaction, making it unlikely to play an important role in modulating the access of aldosterone to mineralocorticoid receptors. Mutations in the HSD11B2 gene (both exonic and intronic) have been demonstrated to cause reduced activity of this enzyme in the syndrome of apparent mineralocorticoid excess, a rare autosomal recessive disorder. We hypothesized that this locus is also involved in the etiology of essential hypertension. To test this locus and flanking chromosomal regions for allelic association and genetic linkage to essential hypertension, it is necessary to have informative genetic markers. To this end, we have refined the localization of 11ß-HSD2 to 16q22.1. We genotyped subjects using the nearest flanking microsatellites (D16S301 and D16S496). We conducted an association study using black subjects with hypertensive end-stage renal disease, black normotensive control subjects, and black and white individuals from the general population. We used ² analysis and Fisher's exact test to test for association with these candidate gene markers. No significant association was found between D16S301 and hypertension. However, a positive association with hypertension was found at the D16S496 microsatellite locus (²=6.98, df=1, P.008). Our data suggest that HSD11B2 is associated with hypertension in our black subjects with hypertensive end-stage renal disease. The 16q22.1 chromosome region potentially harbors a candidate gene for essential hypertension. Confirmation of our findings in another independently ascertained group of hypertensive subjects will provide a basis for proceeding with sib-pair linkage analyses.

Key Words: hypertension, essential • hydroxysteroid dehydrogenase • genetics • hydrocortisone • aldosterone • blacks

	Introduction

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Hypertension is a multifactorial disorder with both genetic and environmental determinants. Although this disorder is a significant cause of morbidity and mortality in the overall US population, blacks have a higher risk of not only developing essential hypertension but also progressing to end-stage renal disease (ESRD).¹ Thus, blacks are of increasing interest for genetic studies of hypertension and are the focus of this study.

As a group, blacks are more prone to develop hypertension, specifically, low-renin, salt-sensitive hypertension.^{2 3} Aberrant responses to excess salt intake among blacks have even been shown in normotensive black family members of individuals with essential hypertension. These normotensive black family members, when given an intravenous salt load, responded with more exaggerated blood pressure increases and slower renal sodium excretion⁴ than whites. This abnormal sodium response may not only be a physiological marker for susceptibility to hypertension but also suggests that candidate genes involved in sodium regulation may have mutations in critical functional regions that will explain subsets of hypertension. We have chosen to examine the association of the 11ß-hydroxysteroid dehydrogenase type 2 gene (HSD11B2) with essential hypertension given its role in the regulation of Na⁺ homeostasis.

11ß-Hydroxysteroid dehydrogenase (11ß-HSD) catalyzes the conversion of C-11 hydroxylated glucocorticoids, including cortisol (the primary glucocorticoid in humans), to the metabolite cortisone. Cortisol has affinity for the mineralocorticoid receptors equivalent to that of aldosterone, the "true" mineralocorticoid in humans. Aldosterone acts through type 1 mineralocorticoid receptors and regulates Na⁺ and K⁺ balance by enhancing reabsorption of Na⁺ and secretion of K⁺ in the distal tubules.⁵ Plasma levels of endogenous cortisol are in 100- to 1000-fold molar excess of those of aldosterone. The 11ß-HSD2 isoform rapidly inactivates cortisol in mineralocorticoid target tissues,^{6 7} and in contrast to the other known human isoform, 11ß-HSD1, its action is unidirectional.^{8 9} 11ß-HSD2, unlike 11ß-HSD1, is highly expressed in the kidney and placenta.^{10 11}

Compromise of 11ß-HSD activity can result in severe hypertension. Such hypertension is exemplified by two disorders: an autosomal recessive disorder, apparent mineralocorticoid excess,¹² and an acquired disorder, licorice-induced hypertension.¹³ Regulation of tissue levels of active glucocorticoids and/or mineralocorticoids may be important in the pathogenesis of essential hypertension.¹³ Mineralocorticoid activity is mediated by the type 1 receptors. Aldosterone is a more potent mineralocorticoid than cortisol; however, they have similar affinities for the type 1 receptor. The type 1 receptor is preferentially occupied by aldosterone when 11ß-HSD2 is functioning properly, ie, effectively converting cortisol to cortisone. When mutations occur in 11ß-HSD2, the receptor sites are preferentially occupied by cortisol, not aldosterone, which then can lead to sodium retention and plasma volume expansion, which in turn suppresses plasma renin and aldosterone secretion.^{6 14} It has been shown that a substitution of the nucleic acid cytosine for thymine in HSD11B2 results in the mutation of arginine 337 to cysteine in a consanguineous family with three siblings affected with apparent mineralocorticoid excess.¹⁵ Finally, it has been shown that mutations in HSD11B2 are responsible for decreased enzyme activity in apparent mineralocorticoid excess.¹⁶ We hypothesize that similar sequence variants within or flanking HSD11B2 will contribute to a portion of the polygenic disorder of essential hypertension in our study population. Our hypothesis is supported by an early study describing hypertensive individuals stratified by suppressed versus nonsuppressed renin activity who had an excess of an unidentified mineralocorticoid that could be speculated to be 11ß-HSD2.¹⁷ Hypertensive patients with suppressed renin activity differed by having higher exchangeable sodium values. These hypertensive patients responded to the adrenal inhibitor aminoglutethimide, which inhibits adrenal secretion of cortisol and aldosterone.¹⁷ Although their aldosterone and desoxycorticosterone secretion rates were normal, the patients seemed to have an undetermined mineralocorticoid excess. Treatment of these patients with aminoglutethimide resulted in reduced blood pressure. This unknown excessive "mineralocorticoid" is suggestive of cortisol.

	Methods

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Subjects
Study subjects were unrelated blacks with ESRD attributable to hypertension (H-ESRD) identified in the dialysis unit of the University of Alabama Hospital. Each person had a history of hypertension before they developed ESRD. Exclusion criteria were diabetes mellitus, adult polycystic kidney disease, Alport's syndrome, homozygosity for hemoglobin S, systemic disease associated with renal involvement, any intravenous drug or cocaine use, abuse of nonsteroidal anti-inflammatory drugs, obstructive uropathy, glomerulonephritis by biopsy, or history compatible with nephrotic syndrome and significant exposure to lead.¹⁸ Blood samples were collected from 79 unrelated H-ESRD individuals who had a mean age of 58.4 years. The mean age of onset of dialysis for the female hypertensive subjects was 53.7±13.5 years and for the male subjects, 49.2±12.2 years.

A group of black normotensive control subjects (n=70) and a black population sample from those who presented for paternity testing (n=98) were used for assessment of allele frequencies and the association of alleles with hypertension. The blood pressures of normotensive control subjects were measured according to the same criteria used for hypertensive subjects. The mean age of the female normotensive control subjects was 35.3±10.2 years and for the males, 39.16±7.7 years. In addition, for the population allele frequency calculations, DNA samples for white individuals (n=89) were also identified from those who presented for paternity testing and were used for analysis. Information regarding the hypertensive status of both the black and white individuals from the paternity testing pool was not available.

The protocol for this study was reviewed and approved by the Institutional Review Board at the University of Alabama at Birmingham.

Refinement of HSD11B2 Chromosomal Assignment and Identification of Flanking Microsatellites
Our chromosomal localization of the HSD11B2 gene was based on polymerase chain reaction (PCR) with the National Institute of General Medical Sciences human/rodent somatic cell mapping panel 2 (Coriell Institute). PCR primers were designed based on the human HSD11B2 cDNA sequence (GenBank accession No. U14631) and were as follows: HSD11B2-3, 5'-TGTGACTCTGGTTTTGGCAAGG-3'; and HSD11B2-4, 5'-TGAACTCTAGCAAGCGGCTAATG-3' (187-bp product). PCR was performed with 100 ng of genomic DNA in a 50-µL reaction volume containing Taq polymerase buffer (10 mmol/L Tris-HCl, 1.5 mmol/L MgCl₂, 50 mmol/L KCl [pH 8.3], 200 mmol/L of each dNTP, 100 pmol/L of each primer, and 0.5 U Taq DNA polymerase [Boehringer Mannheim]). PCR cycling parameters were 35 cycles at 94°C for 1 minute, 60°C for 1 minute, and 72°C for 1.5 minutes followed by a final extension cycle at 72°C for 7 minutes. The same primer set was used with a high-resolution somatic cell hybrid panel for chromosome 16, with an average resolution of 1 Mb for refinement of the localization of this gene and identification of microsatellites as previously described.^{19 20}

Genotype Analysis
DNA was isolated from peripheral blood lymphocytes by the salting-out method.²¹ Genotyping was performed for the microsatellite markers D16S301 and D16S496. These markers map within chromosome region 16q22.1. Genomic DNA (50 ng) was amplified in 10-µL reactions containing 10 pmol/L of each primer and 200 mmol/L of each dNTP with Taq DNA polymerase and buffer. The forward primer was 5' end-labeled. Amplification parameters were 96°C for 5 minutes and then 94°C for 30 seconds, 55°C for 40 seconds, and 72° for 2 minutes for 35 cycles. Before loading, samples were heated to 95°C and snap-chilled on ice. Microsatellites were size-fractionated on a 7% polyacrylamide gel containing 32% formamide and 5.6 mol/L urea.²² Each gel had three M13 sequencing ladders that were used as a standard for sizing unknown alleles. A size/positive control, Centre d'Etudes du Polymorphism Humain (CEPH) individual 1347-02, was included on all gels as well as a negative control lane.

Statistical Methods
Allele frequencies were calculated by counting the number of alleles of each size as a proportion of the total alleles typed. Allele frequency differences among the hypertensive, normotensive, and population samples were evaluated by ² analysis or Fisher's exact test. Since two markers were assessed, we modified the significance level to =0.05/2=0.025. The strength of association of a marker locus was measured by the odds ratio and its associated confidence interval when possible.

	Results

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We refined the localization of HSD11B2 with a high-resolution chromosome 16 somatic cell hybrid mapping panel. Our localization assigned HSD11B2 to chromosome 16, consistent with and independently confirming other reports.^{16 23 24} We localized HSD11B2 to the interval defined by the breakpoints of the hybrids CY4 and CY143. This corresponds to a localization within band 16q22.1. No microsatellites are known in this exact interval; however, immediately proximal is a group of microsatellites as follows: D16S301, D16S397, D16S318, D16S398, D16S347, and D16S421. D16S398 is 0.5 map units proximal to D16S301. The relative order of the other markers could not be reliably determined from analysis of linkage in the CEPH pedigrees. The closest distal marker is D16S496. D16S301 and D16S496 are not separable by recombination in the CEPH pedigrees. They do not recombine even though they are separable on the hybrid map by two hybrid breakpoints and are 1 cM apart on the genetic map and represent flanking markers for this locus.

The frequencies of the alleles of the two closest known flanking microsatellites, D16S301 and D16S496,^{25 26} were determined in blacks and whites who presented to the Immunogenetics/DNA Diagnostic Laboratory for paternity testing. Comparison of the allele frequencies between the two ethnically defined groups was performed with the ² test.²⁷ The allele frequencies at D16S301 for our black sample were significantly different from those for our white sample (²=63.8 at P=.0001; df=9). Similarly, there was also a significant difference when D16S496 allele frequencies were compared between these two populations (²=50.3 at P=.0001; df=14). For the D16S301 locus, we detected 11 alleles ranging in size from 132 to 152 bp. In the case of D16S496, we identified 15 alleles ranging in size from 206 to 234 bp. These results are shown in Tables 1 and 2, respectively.

View this table: [in this window] [in a new window]   Table 1. D16S301 Allele Frequencies Computed for Study Subjects

View this table: [in this window] [in a new window]   Table 2. D16S496 Allele Frequencies Computed for Study Subjects

To assess the importance of these loci in black hypertension, we genotyped black H-ESRD subjects and black normotensive control subjects as well as the group of paternity population control subjects. For a given marker, we were not always successful in getting PCR amplification in all subjects; therefore, the results reported may be based on less than the total n described in "Methods." A ² analysis for D16S301 indicated no significant association of this locus with hypertension. When genotyping results were assessed for D16S496, no overall difference was detected. However, when specific alleles were compared with the remaining totaled alleles, the 216-bp allele exhibited heterogeneity between hypertensive and control subjects (²=6.97 at P=.0083; when Fisher's exact test was used, the value became P=.0084). When correction for two marker (D16S301 and D16S496) comparisons was made for =0.05/2=0.025, significance remained for the D16S496 216-bp allele. An odds ratio and its associated confidence interval could not be calculated because none of the normotensive black control subjects carried this allele.

	Discussion

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We have tested the HSD11B2 locus for association with essential hypertension in a precisely defined population of blacks with essential hypertension, renal failure, and no other systemic disorder. We reasoned that this is a logical candidate gene because (1) it has a role in maintaining sodium homeostasis; (2) biochemical lesions in this gene can result in sodium retention and plasma volume expansion, with subsequent suppression of plasma renin and aldosterone; and (3) salt-sensitive (volume-expanded) and low-renin hypertension occur frequently among blacks.

To test this locus, we had to more precisely localize this gene to identify genetic markers. We have refined the location of the candidate gene, HSD11B2, to 16q22.1 and identified flanking microsatellites. Identification of microsatellites allowed us to test for genetic association at this locus in our black H-ESRD subjects. These results provide evidence for HSD11B2 being involved in the etiology of essential hypertension in black H-ESRD subjects or for the presence of another gene for hypertension in the chromosomal region 16q22.1.

We estimated the frequency of the alleles at D16S301 and D16S496 loci in black (n=97 and n=98, respectively) and white (n=86 and n=89, respectively) populations. No information was available regarding blood pressure status. We would expect that some individuals were at risk for developing essential hypertension in both ethnic groups. Data for the unselected population ethnic control subjects are presented, but because we have no information regarding their blood pressures, we have not used them in our association comparisons. We used only our normotensive control subjects.

The data reveal a significant difference in the frequency of alleles for D16S301 and D16S496 when blacks are compared with whites (D16S301: ²=63.8 at P=.0001, df=9; D16S496: ²=50.3 at P=.0001, df=14). The significance of these frequency differences with respect to essential hypertension association studies in nonblacks remains to be determined.

Genotyping results with D16S301 are shown in Table 1. The ² analysis showed no significant association between this locus and essential hypertension. When individual alleles were compared, still no significant association was detected.

When the microsatellite D16S496 was tested, a statistically significant association was found (²=6.97 at P=.0084 [Fisher's exact test]). There was an increase in the frequency of the 216-bp allele in the H-ESRD subjects and an absence of this allele in the normotensive black control subjects. When the frequency of the 216-bp allele is examined in hypertensive subjects, normotensive control subjects, and the population samples, we note that the allele is present in all groups except the normotensive control subjects. An important caveat is that even though no hypertension was detected in the normotensive control group, a risk remains that some individuals may ultimately become hypertensive. The next step in the evaluation of this locus for an association with essential hypertension is to confirm these results in an independently ascertained set of hypertensive subjects.

In a broader context, the refinement of the chromosome location of the HSD11B2 locus to 16q22.1 together with a statistically significant association between the D16S496 marker and essential hypertension in our black H-ESRD subjects increases our interest in this chromosomal region. Although our initial focus is on the HSD11B2 locus, the possible linkage of these markers to other potential candidate genes for hypertension in this region is intriguing. We cannot rule out the possibility that a gene other than HSD11B2 may be the one actually associated with hypertension. Once markers both proximal and distal to the HSD11B2 locus have been tested, the HSD11B2 association can be confirmed or the importance of other candidate genes in the etiology of essential hypertension in the 16q22.1 region can be discerned. Confirmation of these association data, or data from other genes in this chromosomal region, gives us a basis to proceed to more powerful linkage studies using sib-pair linkage analysis and logarithm of the odds ratio score pedigree analysis using markers and genes in this chromosomal region.

	Acknowledgments

 
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grants DK49228 (B.W.), DK46113 (S.M.B.), and DK48830 (R.T.A.); the University of Alabama–Birmingham Minority Faculty Development Program (B.W.); Alabama Kidney Foundation; and Research Service of the Department of Veterans Affairs (D.G.W.).

Received March 14, 1996; first decision April 2, 1996; accepted May 14, 1996.

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