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

Abstract

11 beta-Hydroxysteroid dehydrogenase type 2 (11 beta-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, 11 beta-HSD2 converts cortisol to cortisone. The other known isoform, 11 beta-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 11 beta-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 chi 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 (chi 2 = 6.98, df = 1, P < or = .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.

Association between a variant in the 11β-hydroxysteroid dehydrogenase type 2 gene and primary hypertension

“…Homozygous carriers of the G534 allele had an age, sex and BMI adjusted OR for hypertension of 1.8 (95%CI = 1.0-3.3) compared with carriers of the other genotypes. The microsatellite marker D16S496 flanking the 11BHSD2 gene, which has earlier been reported to be associated with primary hypertension in blacks, 19 was not associated with hypertension in our study population. There was no linkage disequilibrium between the G534A-and D16S496 markers.…”

“…The fragments were separated on agarose gels after staining with ethidium bromide and visualised under ultraviolet light. A gene segment surrounding the D16S496 microsatellite marker 19,22 was amplified with PCR using a 5Ј-end ␥-32 P-ATP labelled (Amersham, Sweden AB, Solna, Sweden) forward primer (5Ј-TAGTAATAGGATCATACTACTTG) and a reverse primer (5Ј-ATAAGCCACTGCGCCCATC). The primers were designed according to the published genomic sequence surrounding D16S496.…”

“…17,18 A polymorphic Journal of Human Hypertension microsatellite marker flanking the 11BHSD2 gene (D16S496) has been reported to be associated with primary hypertension. 19 We therefore hypothesised that the 11BHSD2 gene could contain variants which decrease the activity of the enzyme and thereby contribute to the pathogenesis of primary hypertension. The aim of this study was to identify variants in the 11BHSD2 gene and to test if such variants or the D16S496 are associated with primary hypertension, in Swedes.…”

Salt-sensitive men show reduced heart rate variability, lower norepinephrine and enhanced cortisol during mental stress

“…[9][10][11][12][13][14] A recent study identified the first naturally occurring polymorphisms in the human HSD11B2 promoter region, with differences in the frequency of polymorphisms between ss and sr subjects. 8 In sum, 11b HSD2 is presumably involved in hypertension as well as in SS, but with a different genetic contribution with respect to the polymorphisms.…”

Apparent mineralocorticoid excess syndrome: an overview

“…One study has reported an association between a microsatellite marker close to the HSD11B2 gene and hypertension in African Americans with hypertensive end stage renal disease (42). These data were confirmed using a polymorphic restriction site in exon 3 of the HSD11B2 gene.…”