title: Association studies between microsatellite markers within the gene encoding human 11beta-hydroxysteroid dehydrogenase type 1 and body mass index, waist to hip ratio, and glucocorticoid metabolism.
abstract: Two isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) interconvert active cortisol (F) and inactive cortisone (E). 11beta-HSD1 is an oxo-reductase (E to F) expressed in several glucocorticoid target tissues, including liver and adipose tissue, where it facilitates glucocorticoid-induced gluconeogenesis and adipocyte differentiation, respectively. We have isolated a full-length HSD11B1 genomic clone; the gene is more than 30 kb in length, not 9 kb in length as previously reported, principally due to a large intron 4. Two polymorphic (CA)(n) repeats have been characterized within intron 4: a CA(19) repeat 2.7 kb 3' of exon 4 and a CA(15) repeat 3 kb 5' of exon 5. The microsatellites, CA(19) and CA(15), were PCR amplified using fluorescent primers and were genotyped on an ABI 377 DNA sequencer from DNA of 413 normal individuals enrolled in the MONICA study of cardiovascular risk factors and 557 Danish men (ADIGEN study), of whom 234 were obese [body mass index (BMI), >/=31 kg/m(2) ] at draft board examination and 323 were randomly selected controls from the draftee population with BMI below 31 kg/m(2) (mean +/- SE, 21.7 +/- 0.41). Genotypic data from the normal MONICA cohort was compared with gender, 5beta-tetrahydrocortisol+5alpha-tetrahydrocortisol/tetrahydrocortisone ratio, and waist to hip (W:H) ratio. When analyzed by allele length (0, 1, or 2 short alleles) for the CA(19) marker, there was a trend toward a higher 5beta-tetrahydrocortisol+5alpha-tetrahydrocortisol/tetrahydrocortisone ratio (P = 0.058) and an increased W:H ratio (2 vs. 0.1 short; P(c) = 0.10) with overrepresentation of short alleles. The opposite was true for the CA(15) locus, with longer alleles at this locus predicting increased 11beta-HSD1 activity, particularly in females. Genotypic data from the ADIGEN case-control population was compared with clinical markers of obesity such as BMI and W:H ratio. There was no significant difference in the distribution of either microsatellite marker between lean and obese groups. Allele distributions were binomial, as seen for the MONICA cohort, and the data were split accordingly (zero, one, or two short alleles). No significant association was seen between grouped alleles and the clinical parameters. No association was observed between HSD11B1 genotype and BMI in either population. These data suggest that 11beta-HSD1 is not a major factor in explaining genetic susceptibility to obesity per se. However, weak associations between HSD11B1 genotype, increased 11beta-HSD1 activity, and W:H ratio suggest that polymorphic variability at the HSD11B1 locus may influence susceptibility to central obesity through enhanced 11beta-HSD1 activity (E to F conversion) in visceral adipose tissue.
authors.affiliation: Division Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom B15 2TH.
authors.forename: N
authors.initials: N
authors.lastname: Draper
authors.forename: S M
authors.initials: SM
authors.lastname: Echwald
authors.forename: G G
authors.initials: GG
authors.lastname: Lavery
authors.forename: E A
authors.initials: EA
authors.lastname: Walker
authors.forename: R
authors.initials: R
authors.lastname: Fraser
authors.forename: E
authors.initials: E
authors.lastname: Davies
authors.forename: T I A
authors.initials: TI
authors.lastname: Sørensen
authors.forename: A
authors.initials: A
authors.lastname: Astrup
authors.forename: J
authors.initials: J
authors.lastname: Adamski
authors.forename: M
authors.initials: M
authors.lastname: Hewison
authors.forename: J M
authors.initials: JM
authors.lastname: Connell
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
authors.forename: P M
authors.initials: PM
authors.lastname: Stewart
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000273:Adipose Tissue; D000293:Adolescent; D000328:Adult; D000483:Alleles; D001823:Body Composition; D001824:Body Constitution / Q000235:genetics*; D015992:Body Mass Index; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D018895:Microsatellite Repeats; D009765:Obesity / Q000235:genetics; D016133:Polymerase Chain Reaction; D014781:Viscera
chemical_list: D005938:Glucocorticoids; D006913:Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human