title: CYP11B2-CYP11B1 haplotypes associated with decreased 11 beta-hydroxylase activity.
abstract: Reduced adrenal 11 beta-hydroxylation has been associated with an aldosterone synthase (CYP11B2) polymorphism. The 11 beta-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 (chi(2) = 2.81; P = 0.09). In vivo 11 beta-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 11 beta-hydroxylase activity.
authors.affiliation: Division of Nephrology, Zoological Institute, University of Berne, Berne 3010, Switzerland.
authors.forename: Santhirasekaran
authors.initials: S
authors.lastname: Ganapathipillai
authors.forename: Guillaume
authors.initials: G
authors.lastname: Laval
authors.forename: Irene S
authors.initials: IS
authors.lastname: Hoffmann
authors.forename: Ana M
authors.initials: AM
authors.lastname: Castejon
authors.forename: Jérôme
authors.initials: J
authors.lastname: Nicod
authors.forename: Bernhard
authors.initials: B
authors.lastname: Dick
authors.forename: Felix J
authors.initials: FJ
authors.lastname: Frey
authors.forename: Brigitte M
authors.initials: BM
authors.lastname: Frey
authors.forename: Luigi X
authors.initials: LX
authors.lastname: Cubeddu
authors.forename: Paolo
authors.initials: P
authors.lastname: Ferrari
mesh_terms: D001483:Base Sequence; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers; D005091:Exons / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D007700:Kinetics; D015810:Linkage Disequilibrium; D010641:Phenotype; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics* / Q000378:metabolism
chemical_list: D017931:DNA Primers; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase