Published Online
on October 30, 2006

A more recent version of this article appeared on January 1, 2007

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Submitted on June 13, 2006
Revised on July 11, 2006

Polymorphic Variation in the 11-Hydroxylase Gene Associates With Reduced 11-Hydroxylase Efficiency

Marianne Barr; Scott M. MacKenzie; Elaine C. Friel; Christine D. Holloway; Donna M. Wilkinson; Nick J.R. Brain; Mary C. Ingram; Robert Fraser; Morris Brown; Nilesh J. Samani; Mark Caulfield; Patricia B. Munroe; Martin Farrall; John Webster; David Clayton; Anna F. Dominiczak; John M.C. Connell^*; and Eleanor Davies

From the British Heart Foundation Glasgow Cardiovascular Research Centre (M.B., S.M.M., E.C.F., C.D.H., D.M.W., N.J.R.B., M.C.I., R.F., A.F.D., J.M.C.C., E.D.), University of Glasgow, Glasgow; Clinical Pharmacology and the Cambridge Institute of Medical Research (M.B., D.C.), University of Cambridge, Addenbrooke’s Hospital, Cambridge; the Department of Cardiovascular Sciences (N.J.S.), University of Leicester, Glenfield Hospital, Leicester; Clinical Pharmacology and Barts and the London Genome Centre (M.C., P.B.M.), William Harvey Research Institute Barts and the London School of Medicine, Charterhouse Square, London; the Nuffield Department of Clinical Medicine and Department of Cardiovascular Medicine (M.F.), University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford; and Medicine and Therapeutics (J.W.), Aberdeen Royal Infirmary, Aberdeen, United Kingdom.

^* To whom correspondence should be addressed. E-mail: J.Connell{at}clinmed.gla.ac.uk.

Abstract--The -344 C/T and intron 2 conversion variants in the CYP11B2 gene, encoding aldosterone synthase, have been associated with markers of impaired 11-hydroxylase activity. We hypothesize that this association is because of variations in the adjacent 11-hydroxylase gene (CYP11B1) and arises through linkage disequilibrium between CYP11B1 and CYP11B2. The pattern of variation across the entire CYP11B locus was determined by sequencing 26 normotensive subjects stratified by and homozygous for the -344 and intron conversion variants. Eighty-three variants associated with -344 and intron conversion were identified. Haplotype analysis revealed 4 common haplotypes, accounting for 68% of chromosomes, confirming strong linkage disequilibrium across the region. Two novel CYP11B1 polymorphisms upstream of the coding region (-1889 G/T and -1859 A/G) were identified as contributing to the common haplotypes. Given the potential for such mutations to affect transcriptional regulation of CYP11B1, these were analyzed further. A total of 512 hypertensive subjects from the British Genetics of Hypertension Study population were genotyped for these polymorphisms. A significant association was identified between the -1889 polymorphism and urinary tetrahydrodeoxycortisol/total cortisol metabolite ratio, indicating reduced 11-hydroxylase efficiency. A similar pattern was observed for the -1859 polymorphism, but this did not achieve statistical significance. Functional studies in vitro using luciferase reporter gene constructs show that these polymorphisms significantly alter the transcriptional response of CYP11B1 to stimulation by adrenocorticotropic hormone or forskolin. This study strongly suggests that the impaired 11-hydroxylase efficiency associated previously with the CYP11B2 -344 and intron conversion variants is because of linkage with these newly identified polymorphisms in CYP11B1.

Key words: hypertension • aldosterone synthase • 11-hydroxylase • polymorphisms • transcriptional regulation

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