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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 1 232-235
Copyright © 2004 by The Endocrine Society

Low Prevalence of the N363S Polymorphism of the Glucocorticoid Receptor in South Asians Living in the United Kingdom

Akheel A. Syed, Julie A. E. Irving, Christopher P. F. Redfern, Andrew G. Hall, Nigel C. Unwin, Martin White, Raj S. Bhopal, K. G. M. M. Alberti and Jolanta U. Weaver

School of Clinical Medical Sciences (A.A.S., N.C.U., K.G.M.M.A., C.P.F.R., J.U.W.), Northern Institute for Cancer Research (J.A.E.I., A.G.H., C.P.F.R.), and School of Population and Health Sciences (N.C.U., M.W.), University of Newcastle, Newcastle upon Tyne NE2 4HH, United Kingdom; and Public Health Sciences Section (R.S.B.), University of Edinburgh Medical School, Edinburgh EH8 9AG, United Kingdom

Address all correspondence and requests for reprints to: Dr. Christopher P. F. Redfern, Medical Molecular Biology Group, 4th Floor, Cookson Building, University of Newcastle Medical School, Newcastle upon Tyne NE2 4HH, United Kingdom. E-mail: chris.redfern{at}ncl.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Similarities between clinical states of glucocorticoid excess and obesity have raised suspicion of a link between the two conditions. An Asn363Ser (N363S) polymorphism in exon 2 of the glucocorticoid receptor has been associated with glucocorticoid sensitivity and excess adiposity in people of European origin. Compared with Europid populations, South Asians have a higher prevalence of cardiovascular risk factors, including type 2 diabetes and central obesity. The aim of this study was to determine the prevalence of the 363S allele in people of South Asian origin living in northeast England in relation to obesity and other cardiovascular risk factors. DNA from 142 males and 153 females was characterized for 363S allele status. Two N363S heterozygotes were identified; both subjects had raised body mass index and central obesity. Despite a higher prevalence of overweight (body mass index >= 25 kg/m2) people in the South Asian group compared with the Europid population in the same geographical area (66 vs. 56%, respectively), the 363S allele frequency was significantly lower in the South Asian group (0.3 vs. 3%, respectively). Therefore, the N363S polymorphism is unlikely to be an important factor in obesity and/or dysmetabolic traits in people of South Asian origin living in the United Kingdom.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
SOME PEOPLE WITH obesity have hormonal, metabolic, and circulatory changes, referred to as the metabolic syndrome, that are also common to patients with glucocorticoid (GC) excess (1). A link between the two conditions, possibly genetic, has therefore been suspected, and the glucocorticoid receptor gene (GRL, 5q31-q32) has been shown to be associated with being overweight (2). Certain alleles, for example the BclI polymorphism, have also been linked to a cluster of cardiovascular risk factors, such as hypertension, insulin resistance, and visceral obesity (3, 4, 5), and to variations in tissue-specific steroid sensitivity (6). The single nucleotide polymorphism N363S is an ATT to GTT missense alteration within exon 2 that results in a receptor variant (GR363S) with an asparagine to serine substitution in a modulatory region; this polymorphism has shown an association with increased sensitivity to GCs (7). Studies from Sydney, Australia, have linked the 363S allele with raised body mass index (BMI) in healthy normotensive adults of Anglo-Celtic descent (8) and, recently, with coronary artery disease (CAD) (9). Our group has found that the polymorphism is associated with central obesity in men in a study involving 375 Europid subjects in northeast England (10). A recent study in French Caucasians with type 2 diabetes mellitus has confirmed an association of the allele with obesity, particularly in men (11). In contrast, studies in Swedish and Danish populations have not found an association of 363S with an altered sensitivity to GCs or with obesity (12, 13).

The clear association between 363S and obesity/CAD suggests that populations with a high prevalence of obesity or other risk factors for CAD, such as South Asians (14, 15, 16, 17), may have a greater prevalence of the allele. The aim of this study was to determine the frequency of 363S in people of South Asian origin living in northeast England in relation to features of the metabolic syndrome.


   Subjects and Methods
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 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study population

Subjects were drawn from the randomly selected, well-characterized Newcastle Heart Project (NHP) that comprised people of several ethnic groups (17). All subjects gave informed, written consent to participate in the NHP. We studied N363S status in 295 South Asian subjects, ranging in age from 26–74 yr (mean, 51 yr), who were seen consecutively as part of the larger study (18, 19). One hundred and three were of Indian origin (35%), 123 were of Pakistani origin (42%), 56 were of Bangladeshi origin (19%), and 13 were of other South Asian origin (4%). Prevalence of the 363S allele in relation to the metabolic syndrome was compared with the Europid subsample comprising 375 subjects (135 men) ranging in age from 27–77 yr (mean, 54 yr) (10). The local research ethics committee approved the study.

Genetic analysis

DNA samples stored in agarose gel from earlier studies of NHP material (18, 19) were re-isolated using a QIAEX II Gel Extraction Kit (QIAGEN Ltd., Crawley, UK) or were freshly extracted from frozen whole blood using Nucleon BACC3 Kit (Tepnel Life Sciences, Manchester, UK). Bases 879 to 1291 of GRL (accession no. NM_000176) were amplified by PCR and analyzed by denaturing HPLC (dHPLC) and/or pyrosequencing. A positive control (363S/363N) and a negative control (no DNA template) were used in every batch.

PCR. PCR amplification of 50–100 ng DNA was performed with 2.5 mM MgCl2, 100 µM deoxynucleoside triphosphates, 0.2 µM each primer, and 1.25 U of Taq polymerase (AmpliTaq Gold; Applied Biosystems, Foster City, CA) in the supplied buffer. PCR primers, optimized for use with dHPLC, were 5'-TTTACCGGACACTAAACCCA (forward) and 5'-TTCGACCAGGGAAGTTCA (reverse). For pyrosequencing, the reverse primer was biotinylated at the 5' end. After an initial 10 min denaturation at 94 C, each PCR cycle was done using denaturation for 20 sec at 94 C and extension for 1 min at 72 C. The annealing temperature was initially 1 min at 63 C decreasing by 1 C every two cycles to 56 C, then 40 cycles at 56 C. Completion of PCR cycles was followed by a 7-min extension at 72 C.

dHPLC. DNA heteroduplexes were generated from PCR products by denaturation (95 C, 5 min) and re-annealed by decreasing the temperature to 4 C at a rate of 1 C every 2 min. Homo- and heteroduplexes (injection volume of 10 µl) were eluted from a DNASep column (Transgenomic Ltd., Crewe, UK) over 4.5 min at 58 C using a gradient of 57–66% buffer B in 0.1 M triethyl ammonium acetate where buffer B was 25% acetonitrile in 0.1 M triethyl ammonium acetate, using a WAVE dHPLC apparatus (Transgenomic Ltd.).

Pyrosequencing. Biotinylated single-stranded DNA was purified from PCRs with streptavidin-coated Sepharose beads (Dynal AS, Oslo, Norway). Sequencing was performed in an automated PSQ96 pyrosequencer (Pyrosequencing AB, Uppsala, Sweden) at 28 C with the primer 5'-CGTTGGTTCCGAAA by sequential addition of deoxynucleoside triphosphates in the dispensation order TGAGTGATA.

Statistical analysis

Data were analyzed using SPSS 11.0 (SPSS Inc., Chicago, IL). Fisher’s exact test was used for comparing the prevalence of the 363S allele in South Asian and Europid populations. Anthropometric and biochemical parameters of South Asian and Europid groups were compared using the two-sample t test.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
A 413-bp region of GRL encompassing codon 363 on exon 2 was amplified from DNA samples of 295 South Asian subjects. PCR products from 209 of these subjects were screened by both dHPLC and pyrosequencing. The two methods gave completely concordant results; all were 363N homozygotes (wild type). Forty-six samples were analyzed by dHPLC alone, of which one was heterozygous for 363S/363N (Fig. 1Go). We are unable to say whether there were any 363S homozygotes in the remaining 45 samples studied by this method alone because the detection of these homozygotes requires samples to be re-run spiked with an equal amount of wild-type 363N DNA for heteroduplex detection. Forty samples were analyzed by pyrosequencing alone, of which one was heterozygous (Fig. 2Go) and the rest were wild type.



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  		FIG. 1. Elution profiles associated with dHPLC analyses of PCR amplicons showing (A) heteroduplex and homoduplex peaks associated with the N363S polymorphism in subject 1 and (B) a single homoduplex peak associated with wild type. The UV detector was set at 254 nm.

 


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  		FIG. 2. Theoretical pyrograms for A/A (A) and A/G (B) genotypes and actual pyrograms from clinical samples demonstrating A/A (C) and A/G (subject 2) genotypes (D). A well-characterized sample with an A/G genotype served as a positive control in each pyrosequencing run. *, SNP position flanked on either side by negative control bases. **, Reference sequence.

 
The frequency of the 363S allele was 0.34% (95% CI, 0.09–1.23%), which was 10-fold lower (P < 0.001) than the frequency in the Europid sample (3.07%; 95% CI, 2.05–4.56%) (10). Phenotypic characteristics of the two South Asian subjects heterozygous for 363S/363N are listed in Table 1Go.


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  		TABLE 1. Anthropometric and biochemical parameters in the two South Asian subjects heterozygous for the 363S allele

 
Differences between South Asian and Europid subjects in the NHP, which have been extensively reported (17), were maintained in the respective subsamples. Because South Asians have a higher percentage of body fat and a more adverse metabolic profile at a lower BMI (20, 21, 22), revised cutoff values for BMI (23 kg/m2), waist circumference (WC; 85 cm in men and 80 cm in women), and waist to hip ratio (WHR; 0.88 in men and 0.81 in women) determined in 10,025 Asian Indian adults from six cities in India have been recommended (23). In the NHP subsample, more South Asian subjects were above these cutoffs compared with Europid subjects, who were assessed by conventional criteria (24, 25). Whereas 84% of South Asian subjects had a BMI of 23 kg/m2 or more (66% >= 25 kg/m2), 56% of subjects in the Europid group had a BMI of 25 kg/m2 or more. Seventy-nine percent and 93% of South Asian men and 77 and 78% of women but 22 and 14% of Europid men and 21 and 0% of women were above the cutoff values for WC and WHR, respectively. Both South Asian N363S heterozygous subjects identified in this study were above the cutoff values for BMI, WC, and WHR, and subject 1 also had impaired fasting glucose and impaired glucose tolerance.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Recent data on fasting serum cortisol concentrations in relation to obesity and the metabolic syndrome suggest that South Asians may be particularly sensitive to the effects of GCs compared with Western populations (26). However, although studies in randomly selected Europid populations have reported a frequency of the 363S allele of 3–7% (7, 8, 10, 11, 12, 13), we have detected a very low prevalence of 0.3% in this heterogeneous population of South Asians made up of 35% people of Indian origin, 42% of Pakistani origin, and 19% of Bangladeshi origin. Given this low prevalence, GR363S is an unlikely mechanism underlying GC sensitivity, obesity, insulin resistance, or other dysmetabolic features in South Asians living in the United Kingdom.

The fact that obesity, defined by the percentage of subjects above the cutoff values, was more prevalent in South Asians mitigates against a selection bias favoring relatively leaner South Asians as an explanation for the low prevalence of the N363S polymorphism. The low prevalence of the 363S allele may result from a low prevalence in the ancestral populations or other factors, such as immigrant bias toward leaner, fitter individuals (who have subsequently acquired obesity due to environmental factors), or differential survival or reproductive success of 363S carriers. Further work is required to address this issue.

Thrifty genes that enable increased fat storage could confer a survival advantage in famine but predispose to obesity, hyperinsulinemia, and glucose intolerance in times of plenty (27). It has been speculated that the 363S allele may be a component of a thrifty genotype (10). Although evidence from various studies (7, 8, 9, 10, 11) suggests that the 363S allele predisposes to obesity, this may depend on genetic background as evidenced by the lack of association observed in the Scandinavian studies (12, 13). Although polymorphisms in the ß2-adrenergic receptor gene have been associated with obesity in several studies (28, 29, 30), we note the lack of association in Danish men (31), drawn from the same cohort as the later (negative) 363S association study (13). On the other hand, a recent study has reported that N363S carriers who also carry the BclI polymorphism tend to have a worse cardiovascular profile (32). Thus, linkage between the 363S allele and other alleles that affect fat storage could explain the observed association between 363S and obesity in some studies whereas there is no association in other studies. Therefore, functional studies of GR363S are required.


   Footnotes
 
Abbreviations: BMI, Body mass index; CAD, coronary artery disease; dHPLC, denaturing HPLC; GC, glucocorticoid; NHP, Newcastle Heart Project; WC, waist circumference; WHR, waist to hip ratio.

Received June 9, 2003.

Accepted September 15, 2003.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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