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Original Article |
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; Pc = 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.
GLUCOCORTICOIDS REGULATE a wide range of physiological functions, including metabolic and homeostatic processes, and form a key component of the stress response. Glucocorticoid action is regulated in part at the prereceptor level by the 11ß-hydroxysteroid dehydrogenase (11ß-HSD) isozymes, which catalyze the interconversion of hormonally active cortisol (F) and inactive cortisone (E) (1). 11ß-HSD1 acts predominantly as an oxo-reductase (E to F) to facilitate glucocorticoid availability to the glucocorticoid receptor (2, 3, 4). The isozyme is widely distributed, with highest expression in liver (5) and adipose tissue (6), where it may play a role in the pathogenesis of insulin resistance and visceral obesity (3, 6, 7). Obesity [defined as a body mass index (BMI) >30 kg/m2 ] is a major risk factor for cardiovascular disease, diabetes, and premature mortality, particularly if body fat is distributed centrally (8). Clinical observations of patients with Cushing’s syndrome reveal that glucocorticoids are involved in regulating body fat distribution, a reversible form of visceral obesity being a discriminatory feature of the disease (9). In previous studies we have defined expression of 11ß-HSD1 in human adipose tissue and shown that expression is highest in omental compared with sc fat (6). Inhibition of 11ß-HSD1 at this site prevented E-induced adipocyte differentiation (10); these findings are endorsed by studies of transgenic mice overexpressing 11ß-HSD1 in adipose tissue (11). Thus, although circulating F concentrations are invariably normal in patients with obesity, the autocrine conversion of E to F by 11ß-HSD1 in adipose tissue, specifically omental fat, may play an important role in central obesity. Conversely, 11ß-HSD2, by inactivating F to E, protects the renal mineralocorticoid receptor from F excess (2). Mutations in the HSD11B2 gene explain an inherited form of hypertension, the syndrome of apparent mineralocorticoid excess, in which F acts as potent mineralocorticoid (2, 12). Recent data have shown a genetic association between a (CA)n microsatellite within intron 1 of the HSD11B2 gene and salt sensitivity, with short alleles at this locus predicting increased salt sensitivity (13). In a similar manner the analysis of polymorphisms within the HSD11B1 gene may be an important tool in elucidating the genetic contribution of this gene to complex disease traits such as central obesity. In this study we isolated a full-length HSD11B1 genomic clone and characterized two polymorphic (CA)n dinucleotide microsatellite repeats, termed CA15 and CA19, within intron 4 of HSD11B1. Studies were then conducted in two separate populations to define any association between HSD11B1 and obesity. We predict that a positive association would indicate a marker in linkage disequilibrium, with a functional variant within the HSD11B1 gene, rather than the markers themselves, influencing gene expression. Intermediate phenotypes, including waist to hip (W:H) ratio and urinary F/E metabolites, have also been studied.
Materials and Methods
Subjects
Two populations were studied: a normal control population and a case-control study from a population of young male draftees.
The MONICA cohort.
The first population consisted of 439 normal individuals (229 men and 210 women) selected as a random sample from North Glasgow, Scotland, from patient lists of 30 general practitioners. Ethical permission for the study was obtained from the local community ethics committee. The subjects were part of the previously described MONICA database examining trends of cardiovascular disease in Scotland (14). BMI and W:H ratio were recorded for each individual. Urinary 5-tetrahydrocortisol (alloTHF), 5ß-tetrahydrocortisol (THF), and tetrahydrocortisone (THE) were measured by 24-h urine collection as previously recorded (14), and the THF+alloTHF/THE ratio was used as a surrogate marker of 11ß-HSD1 activity (15).
The ADIGEN population. The second population, a case-control population, consisted of 557 Danish men with an average age of 19 yr (range, 18–26 yr).
The study population consisted of 2 groups of men, 1 juvenile obese group and 1 control group, previously identified from draft board examination records between 1953 and 1977 in the eastern part of Denmark (16). The 2 groups underwent clinical investigation in 1998–2000. The initial anthropometric examinations were performed at the draft board, which is mandatory for all Danish men aged 18 yr. For the present study 1 group (n = 234) was invited from the juvenile obese group, representing all men with juvenile-onset obesity (BMI, 31 kg/m2) at the draft board. The second group (n = 323) was invited from the original control group (BMI, <31 kg/m2), representing a random sample of 0.5% of all draftees (64,600 men). These subjects were reexamined between 1998–2000, and BMI and W:H ratio were remeasured. From these data the change in BMI per year from draft to ADIGEN examination could be calculated (17). The obese group represents the most obese in this population at the age of draft board examination. As the controls were sampled randomly from the underlying population, they were not necessarily lean, but their BMI distribution reflected the entire population (after exclusion of those identified as obese), and within this, most were lean. All subjects were healthy by self-report and were taking no regular medication.
The Danish Data Surveillance Agency and the ethical committees for Copenhagen and Frederiksberg approved the study. The study was in accordance with the guidelines of the Second Helsinki Declaration. All participants signed a written consent before participating in the study.
Anthropometric estimates
The participants were weighed in their underwear, wearing no shoes, on an electronic scale, and results were recorded to the nearest 0.05 kg. Height was measured to the nearest 0.5 cm with the subject standing against a wall-mounted stadiometer. Hip and waist diameters were measured to the nearest 0.5 cm with the subjects standing, using a nonextendable linen tape measure, according to WHO recommendations.
Identification of two CA repeat polymorphisms within HSD11B1
A genomic library RPC16 was screened using a human 11ß-HSD1 cDNA (gift from Dr. Perrin White, Dallas, TX) (1). This library was prepared from DNA digested by MboI and cloned into a BamHI site of the pPAC4 vector (Roswell Park Cancer Institute, Buffalo, NY). The library has a 4-fold genomic coverage, with an average insert size of 135 kb. DNA from single clones was robot-spotted in duplicate in a unique pattern on polyvinylidene difluoride membranes within a numerical array (Resource Centrum of German Human Genome Project, Berlin, Germany). Original DNA was stored in the same array assignment in 384 well plates corresponding to 92,610 clones. Membranes were hybridized overnight with random primed, 32P-labeled 11ß-HSD1 cDNA in high stringency Church buffer (0.5 mM phosphate/7% SDS) at 65 C. Membranes were then washed with Church and 40 mM phosphate buffers at 65 C and exposed to X-OMAT films (Eastman Kodak Co., Rochester, NY) for 6 h. Coordinates for positive spots were used to select positive clones from the 384-well plates, and the pPAC4 vector was amplified in Escherichia coli strain DH10B. A genomic clone was successfully isolated that contained the entire human HSD11B1 gene (Fig. 1
).
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Genotyping of PCR product containing the two (CA)n microsatellite markers within HSD11B1
Leukocyte DNA was collected from each subject, but sufficient DNA was available for analysis in 413 of the 439 subjects MONICA subjects and in all 557 ADIGEN subjects. Each microsatellite was independently amplified by PCR of genomic DNA using fluorescence-tagged primers. PCR primers flanking the CA15 polymorphism with a 205-bp repeat region were TET-labeled 5'-GGTTGAGGCAGAAGAATCAC-3' (sense) and 5'-GGAGCTGCCATACTATACTG-3' (antisense). The primer pair required to amplify the CA19 microsatellite of 181 bp length were FAM-labeled 5'-GCAATCTCTCCCACATCACC-3' (sense) and 5'-ACTGCCGGATGGAAGGACTT-3' (antisense). Reactions were performed using 50 ng genomic DNA in a 25-µl reaction volume containing 1 mM magnesium chloride, 1x PCR buffer, 8 mM of each deoxy-NTP, and 1 U Hotstar Taq polymerase (QIAGEN, Crawley, UK). The CA15 sense primer was end-labeled with FAM fluorescent dye, and the CA19 sense primer was labeled with TET dye (Oswell, Southampton, UK). Cycling conditions employed an initial 15-min 94 C Taq activation step, followed by 33 cycles of 94 C for 20 sec, 51 C (CA15) or 53 C (CA19) for 20 sec, and 72 C for 20 sec.
Samples were analyzed using an ABI PRISM 377 DNA sequencer (Perkin-Elmer, Warrington, UK) to determine repeat length variation of both microsatellites. Aliquots (1 µl) of PCR product from each amplification were added to 10 µl MilliQ H2O (Millipore UK Ltd, Watford, UK). The combined dilution of PCR products was mixed with 1 U internal size standard labeled with TAMRA fluorescent dye (Genescan-350, PE Applied Biosystems) and resolved on a 5% polyacrylamide gel. The ABI Genescan/Genotyper programs (PE Applied Biosystems) were used to analyze the repeat length of each microsatellite by comparison with the calibration curve of the internal standard.
Statistical analysis
Statistical analysis was carried using the SPSS 10.0 (SPSS, Inc., Chicago, IL) program. Data are presented as the mean ± SE unless stated otherwise. A t test was used for comparison between subgroups of each microsatellite, and P < 0.05 was considered significant. P values were corrected for multiple comparisons (Pc).
Results
Characterization of the HSD11B1 gene
Sequence data from our HSD11B1 clone concurred with those of two overlapping PAC clones submitted to GenBank by the Sanger Center (accession no. AL031316 and AL022398), and the exon and intron sizes of this clone are shown in Fig. 1
. Subsequently, from sequence analyses two (CA)n dinucleotide repeat polymorphisms within intron 4 of HSD11B1 were identified; the first a CA19 positioned 2.7 kb 3' of exon 4, and the second a CA15 approximately 3 kb 5' of exon 5. (The exact locations are noted in our GenBank submission, accession no. AY044083 and AY044084.)
1
MONICA study
The clinical characteristics, urinary corticosteroid metabolites and derived ratios of the MONICA cohort (n = 439) are shown in Table 1. The THF+alloTHF/THE ratio was slightly higher in men (1.18 ± 0.03 vs. 1.05 ± 0.03), compatible with an increase in 11ß-HSD1 in males, but this did not reach statistical significance. For the same BMI, the W:H ratio was higher in men [0.92 ± 0.005 (male) vs. 0.78 ± 0.005 (female); P < 0.001].
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. Heterozygosity values were calculated for both CA15 and CA19 microsatellite repeats; the indexes were 0.43 and 0.46, respectively. The most frequent allele 205 for the CA15 locus (69%) and 181 for the CA19 locus (71%) were in linkage dysequilibrium (P < 0.001, by 
2 test) and could be combined for further analyses. After initial analysis, no relationship was found between an individual allelic genotype and clinical parameters at either the CA15 or CA19 locus. A similar finding was reported in our related studies analyzing HSD11B2 genotypes in patients with salt sensitivity (12). Here, however, an established relationship with allele length was associated with enzyme activity (as determined by the urinary free F/urinary free E ratio) and predisposition to salt sensitivity. Therefore, to further evaluate the relationship between HSD11B1 microsatellite genotypes and subject phenotype, we subdivided the data for the HSD11B1 microsatellites by the number of short alleles (0, 1, or 2 short alleles) at each genotype. The cut-off point for short alleles was placed at the midpoint of allele lengths for each microsatellite repeat, with alleles less than 209 bp at CA19, and those less than 179 bp at CA15 loci classified as being short.
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The data were subdivided for sex due to the established sexual dimorphic nature of the clinical parameters, W:H ratio and THF+alloTHF/THE ratio. The association between short alleles at the CA19 locus and a high THF+alloTHF/THE ratio was significant in females (two vs. zero and one, Pc = 0.05; Fig. 2A). Males (n = 219) with two short alleles at this locus had an increased W:H ratio, but this did not achieve statistical significance (zero and one vs. two short alleles, Pc = 0.12).
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). The genotypic pattern of long CA15 and short CA19 markers individually denoting a raised THF+alloTHF/THE ratio is supported by the alleles 205 (CA15 short allele) and 181 (CA19 long allele) being classed as opposite in length, but acting in linkage disequilibrium. ADIGEN study
Clinical characteristics of the ADIGEN population are shown in Table 3. For the CA15 microsatellite, a total of 19 alleles were observed in 577 subjects. These were named 179–229 (PCR product length), which corresponded to 1–33 (CA)n dinucleotide repeats, respectively. CA19 yielded 18 alleles, with allele lengths of 161–199 corresponding to 3–28 (CA)n repeats. The distribution and relative frequencies for each allele at both microsatellite loci are summarized in Table 4. Heterozygosity values were calculated for the ADIGEN population, with the CA15 index being 0.66, and the CA19 index 0.76, making the markers more polymorphic in the ADIGEN population than within the MONICA cohort. Again, the most frequent allele at the CA15 locus was 205 (56%), but both 179 and 181 alleles were equally frequent at the CA19 locus (34% and 33%, respectively).
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).
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The role of 11ß-HSD isozymes in regulating corticosteroid hormone action in peripheral tissues is well established. The type 2 11ß-HSD dehydrogenase, by inactivating F to E, protects the renal mineralocorticoid receptor from F excess; mutations in the HSD11B2 gene explain an inherited form of hypertension (apparent mineralocorticoid excess), in which F acts as a potent mineralocorticoid (2, 12) despite normal circulating concentrations. Recently, our group and others have characterized polymorphisms within the HSD11B2 gene and demonstrated a possible association between this locus and hypertension in blacks vs. whites (18) and salt sensitivity in both normal subjects and patients with hypertension (13, 19). Conversely, the type 1 isozyme activates F from E in glucocorticoid target tissues, including liver and adipose tissue. Here the enzyme has been shown to enhance glucocorticoid-mediated gluconeogenesis (3) and adipocyte differentiation (10), respectively. Within adipose tissue, 11ß-HSD1 is expressed in high amounts in omental depots (6), and this may account for the predilection of glucocorticoids for visceral obesity. Transgenic mice overexpressing 11ß-HSD1 with adipose tissue are more obese than wild-type littermates and again demonstrate a predilection for visceral obesity (11). We have hypothesized that despite normal circulating F concentrations in obese patients, omental adipose tissue can generate F at an autocrine level via 11ß-HSD1 expression, and this may be an important mechanism underpinning central obesity. Clinical studies are ongoing to test this hypothesis (15), but the characterization of polymorphisms within the human HSD11B1 gene has enabled an evaluation of this locus as a susceptibility factor for obesity in large populations.
Our data on the sequence and structure of this gene are in broad agreement with earlier published studies, with the exception of our detailed characterization of intron 4 (25.4 kb), which establishes that the gene is 30 kb in length, not 9 kb as previously reported, due to cloning in two separate plasmids (1) (now filed with GenBank accession no. AY044083 and AY044084). Using an in-house genomic clone we have characterized polymorphic regions within the HSD11B1 gene. By genotyping a large normal population, no association between the HSD11B1 gene and BMI was demonstrated. Similarly, in a case-control association study evaluating a group of Danish juvenile obese subjects, no relationship between allelic variation at these microsatellite loci and BMI was observed. However, the link between glucocorticoids and adipose tissue biology primarily relates to adipose tissue distribution rather than absolute fat mass. Although urinary steroids were not analyzed in the Danish ADIGEN study, a borderline significant association was found between long alleles for a CA15 microsatellite marker and short alleles for an adjacent CA19 marker in intron 4 of the HSD11B1 gene, with a raised THF+alloTHF/THE ratio and W:H ratio in the MONICA population. These data are compatible with increased 11ß-HSD1 activity predisposing to central obesity. However, a relationship between this allele distribution and central fat distribution was not evident in the ADIGEN study. HSD11B1 genotypes were similar in lean and obese groups, and no relationship was seen with allele length at the two polymorphic loci and with BMI or W:H ratio in either group. Although W:H ratio data were not available from the draft examination, there was no association between HSD11B1 genotype and change in BMI from draft to ADIGEN examination. It is important to note, however, that the ADIGEN study analyzed only males; the Monica group comprised males and females, and associations between HSD11B1 genotypes and W:H ratio were stronger in the latter group.
F metabolism in obesity has been studied in some detail (15, 20, 21). We have previously reported that F metabolite excretion rates showed a positive association with BMI (14). Andrews et al. (22) reported a positive association between 11ß-HSD activity and abdominal girth in men, but not women. However, these findings conflict with our earlier observation, indicating that 11ß-HSD activity was apparently lower (at least in the liver) in subjects with significant obesity (15). It is possible that this reflects the degree of obesity and relative fat distribution in these contrasting studies; the latter observations were based on subjects with a higher BMI than the original dataset. It is noteworthy that animal data and preliminary studies in man suggest that hepatic 11ß-HSD1 is inhibited, but adipose 11ß-HSD1 activity increased, in patients with obesity, and this may result from divergent regulation of 11ß-HSD1 by cytokines (15, 23, 24, 25). Thus, it is possible that the relationship between an indirect measure of "global" 11ß-HSD activity (which will be influenced by both adipose and hepatic enzyme activities) may vary depending upon whether adipose or hepatic activity is most influential. In turn, factors that affect enzyme activity, such as cytokines and insulin, may be key determinants of any relationship.
There is a strong evidence for a genetic component to obesity provided through studies of correlations in BMI and other adiposity measures between family members, between adoptees and their biological relatives, and between monozygotic and dizygotic twins. Monogenic forms of obesity due to mutations notably in the genes encoding leptin, leptin receptor, melanocortin-4 receptor, and proopiomelanocortin have been described. However, the role of genetic factors in common obesity is likely to be polygenic, comprising an interaction between several susceptibility genes that individually have small effects (26). Indeed, over 50 different loci have been linked to obesity through genome scan and linkage studies (26).
In the current study we have failed to demonstrate any association between the HSD11B1 locus and BMI in two separate populations. This might be explained in part by the relatively poor heterozygosity rates for the (CA)n markers, and other markers may prove more fruitful, but the data do suggest that 11ß-HSD1 is not a major factor in explaining genetic susceptibility to obesity per se. However, fat distribution within humans is subject to a wide range of genetic and environmental determinants. Here HSD11B1 may still interact with other genes to predispose to a centrally obese phenotype. In this regard the data linking the HSD11B1 locus to increased W:H ratio were more impressive, particularly in women, and support a role for glucocorticoid activation via 11ß-HSD1 in regulating adipose tissue distribution. Here a weak association between overrepresentation of short alleles at the CA19 locus and long alleles at the CA15 locus and increased 11ß-HSD1 activity and W:H ratio was observed. Thus, polymorphic variability at the HSD11B1 locus may determine susceptibility to central obesity through enhanced 11ß-HSD1 activity (E to F conversion) in visceral adipose tissue.
Acknowledgments
We thank Perrin White for useful suggestions and a critical appraisal of the data.
Footnotes
This work was supported by the Medical Research Council (United Kingdom).
N.D. is a recipient of a Medical Research Council funded studentship.
P.M.S. is a Medical Research Council Senior Clinical Fellow.
Abbreviations: allTHF, 5-Tetrahydrocortisol; E, cortisone; F, cortisol; 3ß-HSD, 11ß-hydroxysteroid dehydrogenase; Pc, P values corrected for multiple comparisons; THE, tetrahydrocortisone; THF, 5ß-tetrahydrocortisol; W:H ratio, waist to hip ratio.
1 These sequence data have been submitted to the GenBank database under accession numbers AY044083 and AY044084. 
Received August 16, 2001.
Accepted July 2, 2002.
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