This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ganapathipillai, S. Articles by Ferrari, P. Search for Related Content PubMed PubMed Citation Articles by Ganapathipillai, S. Articles by Ferrari, P. Related Collections Adrenal and Hypertension

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.

This article has been cited by other articles:

				J. M. C. Connell, S. M. MacKenzie, E. M. Freel, R. Fraser, and E. Davies A Lifetime of Aldosterone Excess: Long-Term Consequences of Altered Regulation of Aldosterone Production for Cardiovascular Function Endocr. Rev., April 1, 2008; 29(2): 133 - 154. [Abstract] [Full Text] [PDF]

				M. Barr, S. M. MacKenzie, E. C. Friel, C. D. Holloway, D. M. Wilkinson, N. J.R. Brain, M. C. Ingram, R. Fraser, M. Brown, N. J. Samani, et al. Polymorphic Variation in the 11{beta}-Hydroxylase Gene Associates With Reduced 11-Hydroxylase Efficiency Hypertension, January 1, 2007; 49(1): 113 - 119. [Abstract] [Full Text] [PDF]

				Wenxia Chai, Y. M Hoedemaekers, R. H. van Schaik, M. van Fessem, I. M Garrelds, J. J Saris, D. Dooijes, F. J ten Cate, M. M. Kofflard, and A. J. Danser Cardiac aldosterone in subjects with hypertrophic cardiomyopathy Journal of Renin-Angiotensin-Aldosterone System, December 1, 2006; 7(4): 225 - 230. [Abstract] [PDF]

				H. Imrie, M. Freel, B. M. Mayosi, E. Davies, R. Fraser, M. Ingram, H. J. Cordell, M. Farrall, P. J. Avery, H. Watkins, et al. Association between Aldosterone Production and Variation in the 11{beta}-Hydroxylase (CYP11B1) Gene J. Clin. Endocrinol. Metab., December 1, 2006; 91(12): 5051 - 5056. [Abstract] [Full Text] [PDF]

				H. Tanahashi, T. Mune, Y. Takahashi, M. Isaji, T. Suwa, H. Morita, N. Yamakita, K. Yasuda, T. Deguchi, P. C. White, et al. Association of Lys173Arg Polymorphism with CYP11B2 Expression in Normal Adrenal Glands and Aldosterone-Producing Adenomas J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6226 - 6231. [Abstract] [Full Text] [PDF]

				P. C. White and W. E. Rainey Polymorphisms in CYP11B Genes and 11-Hydroxylase Activity J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 1252 - 1255. [Full Text] [PDF]