The hypothesis centers on selection of the 11-beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) locus as a candidate gene potentially involved in the etiology of hypertension associated end-stage renal disease in the study population. This hypothesis is based on a number of observations: 1) data suggest HSD11B2 dysfunction may account for the hypertensive phenotype in patients with congenital apparent mineralocorticoid excess (AME), as a consequence of altered cortisol interactions with the mineralocorticoid receptors; 2) altered conversion of cortisol to cortisone in other patients with essential hypertension as measured by [11alpha-3-H]F; and 3) data suggesting that liquorice-induced hypertension with mineralocorticoid effect is associated with inhibition of HSD11B2 by the active agent, glycerrhetinic acid. Preliminary results have localized HSD11B2 to chromosome 16.
The first aim will be to refine the chromosomal location of the HSD11B2 locus, establish linkage to flanking microsatellite sequences, and genotype study subjects at the HSD11B2 locus.
The second aim will be to utilize Woolf's chi-square analysis and genotype relative risk (as well as haplotype relative risk analysis) to evaluate association of specific alleles with risk for developing hypertension. Polymorphisms and mutations will be screened by SSCP and variants sequenced, and in the aggregate, these data will be used to identify informative pedigrees for detailed linkage analysis.
| Watson Jr, B; Bergman, S M; Myracle, A et al. (1996) Genetic association of 11 beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) flanking microsatellites with essential hypertension in blacks. Hypertension 28:478-82 |
