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Association Studies between Microsatellite Markers within the Gene Encoding Human 11ß-Hydroxysteroid Dehydrogenase Type 1 and Body Mass Index, Waist to Hip Ratio, and Glucocorticoid Metabolism

Division Medical Sciences, University of Birmingham, Queen Elizabeth Hospital (N.D., G.G.L., E.A.W., M.H., P.M.S.), Edgbaston, Birmingham, United Kingdom B15 2TH; Steno Diabetes Center and Hagedorn Research Institute (S.M.E., O.P.), DK-2820 Copenhagen, Denmark; Medical Research Council Blood Pressure Group (R.F., E.D., J.M.C.), Glasgow, United Kingdom G11 6NT; Danish Epidemiology Science Center, Institute of Preventive Medicine, Copenhagen University Hospital (T.I.A.S.), DK-1399 Copenhagen, Denmark; Research Department of Human Nutrition, RVA University (A.A.), DK-1958 Frederiksberg, Denmark; and Department of Pediatrics, Institute of Mammal Genetics (J.A.), D85758 Neuherberg, Germany

Address all correspondence and requests for reprints to: Prof. P. M. Stewart, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom B15 2TH. E-mail: p.m.stewart{at}bham.ac.uk.

Abstract

Two isozymes of 11ß-hydroxysteroid dehydrogenase (11ß-HSD) interconvert active cortisol (F) and inactive cortisone (E). 11ß-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 CA₁₉ repeat 2.7 kb 3' of exon 4 and a CA₁₅ repeat 3 kb 5' of exon 5.

The microsatellites, CA₁₉ and CA₁₅, 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/m² ] at draft board examination and 323 were randomly selected controls from the draftee population with BMI below 31 kg/m₂ (mean ± SE, 21.7 ± 0.41). Genotypic data from the normal MONICA cohort was compared with gender, 5ß-tetrahydrocortisol+5-tetrahydrocortisol/tetrahydrocortisone ratio, and waist to hip (W:H) ratio. When analyzed by allele length (0, 1, or 2 short alleles) for the CA₁₉ marker, there was a trend toward a higher 5ß-tetrahydrocortisol+5-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 CA₁₅ locus, with longer alleles at this locus predicting increased 11ß-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 11ß-HSD1 is not a major factor in explaining genetic susceptibility to obesity per se. However, weak associations between HSD11B1 genotype, increased 11ß-HSD1 activity, and W:H ratio suggest that polymorphic variability at the HSD11B1 locus may influence susceptibility to central obesity through enhanced 11ß-HSD1 activity (E to F conversion) in visceral adipose tissue.

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