title: Common polymorphisms in the CYP11B1 and CYP11B2 genes: evidence for a digenic influence on hypertension.
abstract: The locus encompassing the corticosteroidogenic genes CYP11B2 and CYP11B1 is of potential importance in essential hypertension. We analyzed the association of polymorphisms at this locus with risk of essential hypertension, using 2 white case-control collections for discovery (n=3340) and confirmation (n=2929). Single-marker and haplotype analyses were performed, with the CYP11B2 Intron 2 Conversion polymorphism showing strongest association with hypertension in both cohorts and in combined analysis (odds ratio=1.16, P=8.54×10(-5)). The CYP11B1 ACA haplotype associated with increased risk of hypertension relative to the alternative, GTC (odds ratio=1.11; P=7.4×10(-3)), whereas the CYP11B2 TWtC haplotype seemed protective relative to the contrasting CConvT (odds ratio=0.88, P=2.2×10(-3)). Analysis spanning the whole CYP11B1/CYP11B2 locus showed that haplotypes associated with raised risk of hypertension tend to coexist. Functional analysis of heterozygous human adrenal tissue demonstrated decreased CYP11B2 expression and increased CYP11B1 expression for those alleles associating with reduced risk of hypertension. These results confirm the hypertensive influence of this locus, with data suggesting a complex digenic mechanism whereby altered relative CYP11B1 and CYP11B2 gene expression could have a chronic effect on enzyme activity and corticosteroid synthesis.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Samantha
authors.initials: S
authors.lastname: Alvarez-Madrazo
authors.forename: Scott M
authors.initials: SM
authors.lastname: Mackenzie
authors.forename: Eleanor
authors.initials: E
authors.lastname: Davies
authors.forename: Robert
authors.initials: R
authors.lastname: Fraser
authors.forename: Wai-Kwong
authors.initials: WK
authors.lastname: Lee
authors.forename: Morris
authors.initials: M
authors.lastname: Brown
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Caulfield
authors.forename: Anna F
authors.initials: AF
authors.lastname: Dominiczak
authors.forename: Martin
authors.initials: M
authors.lastname: Farrall
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Thomas
authors.initials: T
authors.lastname: Hedner
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Munroe
authors.forename: Nilesh
authors.initials: N
authors.lastname: Samani
authors.forename: Paul M
authors.initials: PM
authors.lastname: Stewart
authors.forename: Björn
authors.initials: B
authors.lastname: Wahlstrand
authors.forename: John
authors.initials: J
authors.lastname: Webster
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
authors.forename: Sandosh
authors.initials: S
authors.lastname: Padmanabhan
authors.forename: John M
authors.initials: JM
authors.lastname: Connell
mesh_terms: D000293:Adolescent; D000311:Adrenal Glands / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics* / Q000378:metabolism
chemical_list: D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase