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CYP11B2-CYP11B1 Haplotypes Associated with Decreased 11ß-Hydroxylase Activity

Division of Nephrology (S.G., J.N., B.D., F.J.F., B.M.F., P.F.) and Computational and Molecular Population Genetics Laboratory (G.L.), Zoological Institute, University of Berne, Berne 3010, Switzerland; Clinical Pharmacology Unit, Central University of Venezuela (I.S.H., A.M.C., L.X.C.), Caracas 1050, Venezuela; and Department of Nephrology, Fremantle Hospital, University of Western Australia (P.F.), Perth, Western Australia 6160, Australia

Address correspondence and requests for reprints to: Dr. Paolo Ferrari, School of Medicine and Pharmacology, University of Western Australia, and Department of Nephrology, Fremantle Hospital, Alma Street, Perth, Western Australia 6160, Australia. E-mail: paolo.ferrari{at}health wa.gov.au.

Reduced adrenal 11ß-hydroxylation has been associated with an aldosterone synthase (CYP11B2) polymorphism. The 11ß-hydroxylase gene (CYP11B1) lies close to CYP11B2. We hypothesize that a molecular variant in CYP11B2 is in linkage disequilibrium (LD) with a key quantitative trait in CYP11B1 determining this phenotype. Polymorphisms and inferred haplotypes at CYP11B loci were studied in two independent populations from Europe (n = 100) and South America (n = 99). The latter underwent detailed hormonal studies. LD was estimated by alternative Bayesian methods for inferring the extent of LD when haplotypes at different loci are inferred. Population differences in single nucleotide polymorphisms were modest, indicating the stability of both genes across populations. Using five of nine potentially informative loci at CYP11B sites with allele frequency greater than 0.1, two major contrasting haplotypes, CwtCG and TconvGTA, were found. In both populations the CwtCG haplotype accounted for 44% and the TconvGTA for 32% of subjects. Haplotype distribution did not differ between Europeans and South Americans (² = 2.81; P = 0.09). In vivo 11ß-hydroxylase activity, estimated from urinary steroid profiling, was lower in subjects with an increased aldosterone to renin ratio or with the TconvGTA haplotype. These findings indicate that genotypes at the CYP11B locus are in strong LD and that identified haplotypes predict 11ß-hydroxylase activity.

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