title: Polymorphic variation in the 11beta-hydroxylase gene associates with reduced 11-hydroxylase efficiency.
abstract: The -344 C/T and intron 2 conversion variants in the CYP11B2 gene, encoding aldosterone synthase, have been associated with markers of impaired 11beta-hydroxylase activity. We hypothesize that this association is because of variations in the adjacent 11beta-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 11beta-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 11beta-hydroxylase efficiency associated previously with the CYP11B2 -344 and intron conversion variants is because of linkage with these newly identified polymorphisms in CYP11B1.
authors.affiliation: British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, UK.
authors.forename: Marianne
authors.initials: M
authors.lastname: Barr
authors.forename: Scott M
authors.initials: SM
authors.lastname: MacKenzie
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Friel
authors.forename: Christine D
authors.initials: CD
authors.lastname: Holloway
authors.forename: Donna M
authors.initials: DM
authors.lastname: Wilkinson
authors.forename: Nick J R
authors.initials: NJ
authors.lastname: Brain
authors.forename: Mary C
authors.initials: MC
authors.lastname: Ingram
authors.forename: Robert
authors.initials: R
authors.lastname: Fraser
authors.forename: Morris
authors.initials: M
authors.lastname: Brown
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Mark
authors.initials: M
authors.lastname: Caulfield
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Munroe
authors.forename: Martin
authors.initials: M
authors.lastname: Farrall
authors.forename: John
authors.initials: J
authors.lastname: Webster
authors.forename: David
authors.initials: D
authors.lastname: Clayton
authors.forename: Anna F
authors.initials: AF
authors.lastname: Dominiczak
authors.forename: John M C
authors.initials: JM
authors.lastname: Connell
authors.forename: Eleanor
authors.initials: E
authors.lastname: Davies
mesh_terms: D000305:Adrenal Cortex Hormones / Q000652:urine; D000328:Adult; D000368:Aged; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics*; D004837:Epinephrine; D015870:Gene Expression; D005787:Gene Frequency; D005838:Genotype; D006147:Guanine; D006239:Haplotypes; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics* / Q000378:metabolism*; D013941:Thymine
chemical_list: D000305:Adrenal Cortex Hormones; D006147:Guanine; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase; D013941:Thymine; D006854:Hydrocortisone; D004837:Epinephrine