This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dobson, M. G. Articles by Weaver, J. U. Search for Related Content PubMed PubMed Citation Articles by Dobson, M. G. Articles by Weaver, J. U.

The N363S Polymorphism of the Glucocorticoid Receptor: Potential Contribution to Central Obesity in Men and Lack of Association with Other Risk Factors for Coronary Heart Disease and Diabetes Mellitus¹

Departments of Endocrinology (M.G.D., C.P.F.R.) and Diabetes (J.U.W., N.U.), Medical School, and Queen Elizabeth Hospital, Gateshead (J.U.W.), University of Newcastle, Newcastle upon Tyne NE2 4HH, United Kingdom

Address all correspondence and requests for reprints to: C. P. F. Redfern, Ph.D., Medical Molecular Biology Group, 4th Floor, Cookson Building, University of 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

 
Considerable evidence suggests that diabetes mellitus and hypertension are influenced by genetic factors. Studies in humans have associated glucocorticoid receptor (GR) polymorphisms with high blood pressure, insulin sensitivity, body mass index, increased visceral fat, and variations in tissue-specific steroid sensitivity. The N363S polymorphism of the GR results in an asparagine to serine amino acid substitution in a modulatory region of the receptor. Phosphorylation of serine residues in this region has been shown to enhance transactivation of GR responsive genes. The aim of this study was to investigate the association between the 363S allele and risk factors for coronary heart disease and diabetes mellitus in a population of European origin living in the northeast of the United Kingdom. Blood samples from 135 males and 240 females were characterized for 363 allele status. The overall frequency of the 363S allele was 3.0%, 23 heterozygotes (7 males and 16 females) but no 363S homozygotes were identified. The data show a significant association of the 363S allele with increased waist to hip ratio in males but not females. This allele was not associated with blood pressure, body mass index, serum cholesterol, triglycerides, low-density lipoprotein and high-density lipoprotein cholesterol levels, and glucose tolerance status. The results of this study suggest that this GR polymorphism may contribute to central obesity in men. Further studies are required to elucidate the properties of GR_363S at a molecular level.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
CORONARY HEART DISEASE (CHD) and diabetes mellitus (DM) are likely to be multifactorial disorders influenced by both environmental and genetic factors. Therapy with glucocorticoids may be associated with obesity, glucose intolerance, and hypertension (1, 2), and Cushing’s syndrome, the clinical manifestation of glucocorticoid excess, is also associated with increased cardiovascular morbidity and mortality (3). Several potential disease-causing loci with varying degrees of association with endogenous and environmental risk factors have been identified. Different alleles at these loci may predispose an individual to risk factors for diseases such as DM or CHD in response to environmental factors (4, 5). It has been speculated that because DM and CHD share a number of risk factors, such as obesity, fat distribution, and hypertension, they may originate from the same antecedents, which may be genetically determined (4, 6, 7).

Studies in humans have suggested a positive association between hypertension, obesity and glucose tolerance, with alleles at the glucocorticoid receptor (GR) locus. For example, the BclI polymorphism within the intron upstream of GR exon II has been associated with the CHD risk factors such as high blood pressure, insulin sensitivity, body mass index (BMI), and fat distribution (8, 9). Other groups have confirmed that this polymorphism is associated with increased visceral fat (10) and with variations in tissue-specific steroid sensitivity (11). Thus, GR variation has been postulated as a source of variation that may be relevant to the progression to DM and CHD phenotypes. In contrast to the intronic BclI polymorphism, the N363S polymorphism of the GR is situated within exon 2 and results in an asparagine to serine substitution. This N-terminal domain of the receptor modulates transcriptional activation, and hyperphosphorylation of serine residues could enhance glucocorticoid-regulated gene expression (12). In elderly subjects, the 363S allele has been associated with cortisol hyperreactivity, as defined by an increased insulin secretion following dexamethasone (13), and was recently associated with increased BMI in a cohort of 195 healthy normotensive Australians (14).

Despite these studies the functional significance of N363S in risks for CHD and DM is unknown. The aim of this work was to elucidate the relationship between the various risk factors for CHD and the 363S polymorphism in a well-characterized population in the United Kingdom.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Study population

Blood samples from 375 healthy British people on no medication were studied from the randomly selected Newcastle Heart Project (NHP) subjects (15, 16). Although the NHP included many ethnic groups, only those of European origin were studied to avoid complications arising from differences in cardiovascular risk factors between different ethnic populations. The study was approved by the local Ethics Committee and subjects gave their consent. DNA prepared from the blood samples was used to determine GR genotype. All data on the phenotype were obtained from the NHP database as previously described (15, 16). The sample consisted of 135 men and 240 women, ranging in age from 27 to 77 yr, and for whom a blood sample and measurements of height, weight, blood pressure, waist to hip ratio, BMI, serum cholesterol, triglycerides, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels, and insulin and glucose levels at fasting and 1 and 2 h after a 75-g oral glucose load [oral glucose tolerance (OGT)] were available. In addition, the ratio of fasting insulin to glucose was used as a measure of insulin sensitivity. Homeostasis model assessment (HOMA) of insulin resistance (HOMA-IR) and ß-cell function were calculated (17) and used in place of fasting insulin levels in multivariate analyses. Although there were 825 subjects of European origin in the NHP, only 375 were available for the study. A few values of some of the variables are missing for some patients and this slightly reduced the sample sizes for some statistical analyses. A summary of the data is shown in Table 1.

DNA was extracted from whole blood by conventional phenol/chloroform extraction. A 357-bp area of exon 2 of the GR gene was amplified from genomic DNA by PCR using previously described primers (18); sequencing quality was improved by adding bases complementary to M13 sequencing primers to the 5' end of each primer. PCR products were sequenced in the forward and reverse directions in the University of Newcastle Molecular Biology Unit using an PE Applied Biosystems (Warrington, UK) automated sequencer. A to G transitions at base¹²²⁰ of the GR gene (2nd base of codon 363) were identified from sequencing data and confirmed by digesting PCR products with Tsp509I, which gives 19- and 73-bp fragments for the A¹²²⁰ allele and a 92-bp fragment for the G¹²²⁰ allele (14). Digests were separated by electrophoresis through 20% polyacrylamide gels (Acrylogel 3 solution, BDH, Lutterworth, UK), and the bands were visualized by silver staining. The single nucleotide polymorphism at base 1220, codon 363, is referred to throughout this paper as 363N for the wild-type (A¹²²⁰) allele and 363S for the G¹²²⁰ allele.

Statistical analysis

Data were analyzed using the Systat (SPSS, Inc., Chicago, IL) statistical package. Differences between proportions were tested by a ² test, and 95% confidence intervals for differences between proportions were calculated from the log-odds ratios. For analysis of continuous variables by multivariate methods, departures from normality were tested by the Kolmogorov-Smirnov test (Lillefors modification). Natural logarithm or reciprocal transformations were applied to normalize dependent variates, as appropriate, and parametric statistics were used to analyze the transformed data. For multiple regression with general linear models the independent variates were physiological variables log-transformed to minimize the influence of outliers; stepwise backward multiple regression was performed with an F-ratio probability of 0.10 as the criterion for removal or inclusion in the model. Where multiple regression was performed separately for each sex, Bonferroni correction was used to maintain an experiment-wise error rate of 0.05. Analysis of covariance (ANCOVA) and multiple ANCOVA (MANCOVA) were used to look for differences in obesity and physiological variables in relation to 363S status.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
363S allele frequency in relation to obesity

Blood samples from 375 subjects were analyzed to determine the frequency of the N363S polymorphism and 23 363S/363N heterozygotes (7 males and 16 females) were identified, an overall allelic frequency of 3.0% (Fig. 1). No 363S homozygotes were identified. Lin et al. (14) found a significant association of 363S carrier status with obesity (BMI > 25) in an Australian population from Sydney. In contrast, in the present study population, 9 of 169 subjects with BMI less than or equal to 25 and 14 of 209 subjects with BMI more than 25 were heterozygous for N363S, and there was no association of the 363S allele with BMI (₁² = 0.28, P = 0.6). Furthermore, there was a significant 4.4% difference in allele frequency between the Newcastle (3%) and Sydney (7.4%) (14) populations (₁² = 10.45, P < 0.005; 95% confidence interval 1.12–18.8 for the difference in proportion of 363S carriers between Newcastle and Sidney).

View larger version (35K): [in this window] [in a new window]   Figure 1. DNA sequencing chromatogram from a 363N (wild-type) homozygous individual (A) and a 363S/363N heterozygote (B). The single nucleotide polymorphism is marked with an arrow.

The 363S allele in relation to diabetes and insulin sensitivity

It has been reported previously that 363S carriers show a significantly higher insulin response to a dexamethasone suppression test (13). To investigate a possible association of the 363S allele with diabetes, plasma glucose levels 2 h after an OGT test were used to divide subjects into diabetic (2-h plasma glucose 11.1 mmol/L, n = 15), nondiabetic (2-h plasma glucose < 7.8, n = 293) and impaired glucose tolerance (2-h plasma glucose 7.8 and <11.1 mmol/L, n = 54) groups. A few individuals who did not undergo an OGT test were classified on the basis of fasting glucose (diabetic 7.0 mmol/L, n = 11; impaired glucose tolerance 6.1 mmol/L and <7.0 mmol/L, n = 0; nondiabetic < 6.1 mmol/L, n = 2) (19). There was no difference in 363S allele frequency between each group (₂² = 0.176, P > 0.9).

To test for an association between the 363S allele and insulin response, serum insulin concentrations 2 h after an OGT test were compared between 23 363S/363N heterozygotes and 337 wild-type homozygotes. Serum insulin levels were significantly related to BMI (linear regression of log-transformed 2-h insulin levels against BMI, F_1,358 = 77.14, P < 0.00001) and ANCOVA was used to correct for the effects of body weight. There was no significant difference in 2-h serum insulin response between the 363S carriers and wild-types (F_1,357 = 0.047, P > 0.8). Insulin sensitivity (fasting insulin/fasting glucose) was significantly related to body weight (ANOVA F_1,372 = 187.07, P < 0.00001), and after correcting for the effects of body weight there was no significant difference in insulin sensitivity between wild-type homozygotes and 363S/363N heterozygotes (ANCOVA F_1,371 = 0.019, P = 0.9).

The 363S allele in relation to blood pressure

A BclI polymorphism of GR exon II has been associated with increased blood pressure (8). In the Newcastle study population, data for mean systolic, mean diastolic (mean of measurements on two occasions), and mean arterial blood pressure were significantly related to age (F_1,369 17.5, P 0.0001 for linear regression of log-diastolic and reciprocal transformations of systolic and mean arterial blood pressures against age). Correcting for the effects of age, there was no significant difference between the 363S carriers and wild-type homozygotes with respect to blood pressure (ANCOVA, F_1,368 0.35, P > 0.5).

Association between 363S and central obesity

Waist to hip ratio was used as a measure of central obesity; in this study population, the distribution of waist to hip ratios was bimodal, with significant differences in median ratio between males (median 0.927) and females (median 0.783, Mann-Whitney U test 29113.5, P < 0.000001). For males, waist to hip ratios were normally distributed (P > 0.9). In multiple regression analysis, age, serum triglycerides, 1-hr insulin, fasting glucose, and BMI (all except age log-transformed) explained 64.4% of the variance in waist to hip ratio for males (Table 2). After correcting for the effects of these variables, 363S heterozygotes had a significantly greater waist to hip ratio (0.962 ± 0.016, n = 7) than wild-type homozygotes (0.919 ± 0.004, n = 122; MANCOVA F_1,122 = 6.87, P < 0.01). Clearly, despite the small number of 363S heterozygotes, this GR gene polymorphism made a significant contribution (Bonferroni-corrected P < 0.02) to variance in waist to hip ratio in males.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

In a cohort of 195 normotensive white Australian subjects of British descent, Lin et al. (14) recently observed that the 363S allele was associated with general obesity being present in 80% of subjects with a BMI greater than 25. Although Huizenga et al. (13) also observed a higher mean BMI for 363S carriers, we were unable to confirm this association in a population with similar characteristics from the northern region of the United Kingdom. Data for central obesity were not reported in the previous studies and further comparisons are not possible. However, we postulate that the observed association of BMI with the 363S allele was related to a correlation between central obesity and BMI; whereas these studies associated BMI and 363S, what was really observed was an effect of central obesity on BMI. Conversely, the 363S allele frequency was significantly different between the Newcastle population and Sidney cohorts and the low frequency of the allele in the Newcastle population may mitigate against detecting a weak association with BMI. Genetic differences between study populations may also contribute to any association between 363S and BMI. For example, alleles at the adjacent (1 cM) ß₂-adrenoceptor locus have been associated with obesity (26, 27) and linkage between particular ß₂-adrenoceptor alleles and the 363S allele could explain the observed association between 363S and BMI in the Sidney study. Other differences between the study populations, such as variables that contribute to BMI (diet and exercise for example), may also contribute to the likelihood of detecting an association with the 363S allele.

It has been suggested that altered steroid metabolism in favor of cortisol in adipocytes may underlie the development of visceral obesity (28). GR_363S has a serine residue replacing arginine in the N-terminal (modulatory) region of the receptor, and this may affect cortisol-dependent receptor activity. It has been reported, on the basis of transient transfection experiments, that functional alteration of the GR_363S receptor compared with wild-type is not detectable (29). However, phosphorylation of GR serine residues decreases the half-life of the receptor in the mouse (30) and other studies have shown that phosphorylation strongly enhances transactivating activity of the receptor (12). Thus, increased transcriptional activation activity of GR_363S, possibly as a result of phosphorylation of the substituted serine residue, may be a mechanism for an enhanced effect of cortisol on fat deposition in men. Although the N363S polymorphism did not associate with other risk factors for CHD and DM, it may contribute to these diseases via central obesity. The 363S allele may be a component of a thrifty genotype which could be a selective advantage (31, 32) in famine, but in times of plenty this allele may predispose toward obesity and CHD.

	Acknowledgments

 
We thank the nursing and medical team from Wellcome Research laboratories at Royal Victoria Infirmary (Newcastle upon Tyne, UK) for clinical and biochemical assessment of the studied population and Prof. John Matthews of the Department of Mathematics and Statistics (University of Newcastle, Newcastle upon Tyne, UK) for advice on statistical methodology.

	Footnotes

 
¹ This work was supported by the Diabetes Fund (Queen Elizabeth Hospital, Gateshead, UK).

Received September 19, 2000.

Revised January 24, 2001.

Accepted January 30, 2001.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Walker BR, Connacher AA, Webb DJ, Edwards CR. 1992 Glucocorticoids and blood pressure: a role for the cortisol/cortisone shuttle in the control of vascular tone in man. Clin Sci. 83:171–178.[Medline]
2. Nordborg E, Schaufelberger C, Bosaeus I. 1998 The effect of glucocorticoids on fat and lean tissue masses in giant cell arteritis. Scand J Rheumatol. 27:106–111.[CrossRef][Medline]
3. Etxabe J, Vazquez JA. 1994 Morbidity and mortality in Cushing’s disease: an epidemiological approach. Clin Endocrinol. 40:479–484.[Medline]
4. Turner RC, Levy JC, Clark A. 1993 Complex genetics of type 2 diabetes: thrifty genes and previously neutral polymorphisms. Q J Med. 86:413–417.[Free Full Text]
5. Sankaranarayanan K, Chakraborty R, Boerwinkle EA. 1999 Ionizing radiation and genetic risks VI. Chronic multifactorial diseases: a review of epidemiological and genetical aspects of coronary heart disease, essential hypertension and diabetes mellitus. Mutat Res. 436:21–57.[CrossRef][Medline]
6. Panarelli M, Fraser R. 1994 The glucocorticoid receptor and hypertension. Endocr Res. 20:101–116.[Medline]
7. Stern MP. 1995 Diabetes and cardiovascular disease. Diabetes. 14:369–374.
8. Watt GCM, Harrap SB, Foy CJ, et al. 1992 Abnormalities of glucocorticoid metabolism and the Renin-Angiotensin system: a four-corners approach to the identification of genetic determinants of blood pressure. J Hypertens. 10:473–482.[Medline]
9. Weaver JU, Hitman GA, Kopelman PG. 1992 An association between a Bcl I restriction fragment length polymorphism of the glucocorticoid receptor locus and hyperinsulinaemia in obese women. J Mol Endocrinol. 9:295–300.[Abstract]
10. Buemann B, Vohl MC, Chagnon M, et al. 1997 Abdominal visceral fat is associated with a BclI restriction fragment length polymorphism at the glucocorticoid receptor gene locus. Obes Res. 5:186–192.[Medline]
11. Panarelli M, Holloway CD, Fraser R, et al. 1998 Glucocorticoid receptor polymorphism, skin vasoconstriction, and other metabolic intermediate phenotypes in normal human subjects. J Clin Endocrinol Metab. 83:1846–1852.[Abstract/Free Full Text]
12. Bodwell JE, Webster JC, Jewell CM, Cidlowski JA, Hu JM, Munck A. 1998 Glucocorticoid receptor phosphorylation: overview, function and cell cycle-dependence. J Steroid Biochem Mol Biol. 65:91–99.[CrossRef][Medline]
13. Huizenga NATM, Koper JW, Lange PD, et al. 1998 A polymorphism in the glucocorticoid receptor gene may be associated with an increased sensitivity to glucocorticoids in vivo. J Clin Endocrinol Metab. 83:144–151.[Abstract/Free Full Text]
14. Lin RCY, Wang WYS, Morris BJ. 1999 High penetrance, overweight, and glucocorticoid receptor variant: case-control study. Br Med J. 319:1337–1338.[Free Full Text]
15. Harland JO, Unwin N, Bhopal RS, et al. 1997 Low levels of cardiovascular risk factors and coronary heart disease in a UK Chinese population. J Epidemiol Community Health. 51:636–642.[Abstract]
16. Unwin N, Harland J, White M, et al. 1997 Body mass index, waist circumference, waist-hip ratio, and glucose intolerance in Chinese and Europid adults in Newcastle, UK. J Epidemiol Community Health. 51:160–166.[Abstract]
17. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. 1985 Homeostasis model assessment: insulin resistance and cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 28:412–419.[CrossRef][Medline]
18. Koper JW, Stolk RP, De Lange P, et al. 1997 Lack of association between five polymorphisms in the human glucocorticoid receptor gene and glucocorticoid resistance. Hum Genet. 99:663–668.[CrossRef][Medline]
19. WHO Expert Committee on Diabetes Mellitus. 1999 Definition, diagnosis and classification of diabetes mellitus and its complications. In: Alberti KGMM, Zimmet PZ (chairmen). Report of a WHO consultation. Part 1: diagnosis and classification of diabetes mellitus. Geneva: WHO; 1–59.
20. Lemieux S, Prud’homme D, Bouchard C, Tremblay A, Despres JP. 1993 Sex differences in the relation of visceral adipose tissue accumulation to total body fatness. Am J Clin Nutr. 58:463–467.[Abstract/Free Full Text]
21. Haarbo J, Marslew U, Gotfredsen A, Christiansen C. 1991 Postmenopausal hormone replacement therapy prevents central distribution of body fat after menopause. Metabolism. 40:1323–1326.[CrossRef][Medline]
22. Lonn L, Kvist H, Ernest I, Sjostrom L. 1994 Changes in body composition and adipose tissue distribution after treatment of women with Cushing’s syndrome. Metabolism. 43:1517–1522.[CrossRef][Medline]
23. Björntorp PA. 1999 Overweight is risking fate. Bailliere’s Clin Endocrinol Metab. 13:47–69.
24. Rosmond R, Dallman MF, Björntorp P. 1998 Stress-related cortisol secretion in men: relationships with abdominal obesity and endocrine, metabolic and hemodynamic abnormalities. J Clin Endocrinol Metab. 83:1853–1859.[Abstract/Free Full Text]
25. Björntorp P, Rosmond R. 2000 Obesity and cortisol. Nutrition. 16:924–936.[CrossRef][Medline]
26. Timmermann B, Mo R, Luft FC, et al. 1998 ß₂ adrenoceptor genetic variation is associated with genetic predisposition to essential hypertension: the Bergen blood pressure study. Kidney Int. 53:1455–1460.[CrossRef][Medline]
27. Hellström L, Large V, Reynisdottir S, Wahrenberg H, Arner P. 1999 The different effects of a Gln²⁷Glu ß₂-adrenoceptor gene polymorphism on obesity in males and in females. J Intern Med. 245:253–259.[CrossRef][Medline]
28. Bujalska IJ, Kumar S, Stewart PM. 1997 Does central obesity reflect "Cushing’s disease of the omentum"? Lancet. 349:1210–1213.[CrossRef][Medline]
29. Ray DW, Davis JR, White A, Clark AJ. 1996 Glucocorticoid receptor structure and function in glucocorticoid-resistant small cell lung carcinoma cells. Cancer Res. 56:3276–3280.[Abstract/Free Full Text]
30. Hu JM, Bodwell JE, Munck A. 1997 Control by basal phosphorylation of cell cycle-dependent, hormone-induced glucocorticoid receptor hyperphosphorylation. Mol Endocrinol. 11:305–311.[Abstract/Free Full Text]
31. O’Dea K. 1995 Overview of the thrifty genotype hypothesis. Asia Pacific J Clin Nutrition. 4:339–340.
32. Swinburn BA. 1996 The thrifty genotype hypothesis: how does it look after 30 years? Diabetes Med. 13:695–699.[CrossRef][Medline]

This article has been cited by other articles:

				A. S. Tait, C. L. Butts, and E. M. Sternberg The role of glucocorticoids and progestins in inflammatory, autoimmune, and infectious disease J. Leukoc. Biol., October 1, 2008; 84(4): 924 - 931. [Abstract] [Full Text] [PDF]

				M. J. J. Finken, I. Meulenbelt, F. W. Dekker, M. Frolich, J. A. Romijn, P. E. Slagboom, J. M. Wit, and on behalf of the Dutch POPS-19 Collaborative Study The 23K Variant of the R23K Polymorphism in the Glucocorticoid Receptor Gene Protects against Postnatal Growth Failure and Insulin Resistance after Preterm Birth J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4777 - 4782. [Abstract] [Full Text] [PDF]

				R. Felder-Puig, C. Scherzer, M. Baumgartner, M. Ortner, C. Aschenbrenner, C. Bieglmayer, T. Voigtlander, E. R. Panzer-Grumayer, W. J.E. Tissing, J. W. Koper, et al. Glucocorticoids in the Treatment of Children with Acute Lymphoblastic Leukemia and Hodgkin's Disease: A Pilot Study on the Adverse Psychological Reactions and Possible Associations with Neurobiological, Endocrine, and Genetic Markers Clin. Cancer Res., December 1, 2007; 13(23): 7093 - 7100. [Abstract] [Full Text] [PDF]

				B. R Walker Glucocorticoids and Cardiovascular Disease Eur. J. Endocrinol., November 1, 2007; 157(5): 545 - 559. [Abstract] [Full Text] [PDF]

				C. M. Jewell and J. A. Cidlowski Molecular Evidence for a Link between the N363S Glucocorticoid Receptor Polymorphism and Altered Gene Expression J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 3268 - 3277. [Abstract] [Full Text] [PDF]

				Z. Michailidou, A. P Coll, C. J Kenyon, N. M Morton, S. O'Rahilly, J. R Seckl, and K. E Chapman Peripheral mechanisms contributing to the glucocorticoid hypersensitivity in proopiomelanocortin null mice treated with corticosterone J. Endocrinol., July 1, 2007; 194(1): 161 - 170. [Abstract] [Full Text] [PDF]

				A. Rautanen, J. G. Eriksson, J. Kere, S. Andersson, C. Osmond, P. Tienari, H. Sairanen, D. J. P. Barker, D. I. W. Phillips, T. Forsen, et al. Associations of Body Size at Birth with Late-Life Cortisol Concentrations and Glucose Tolerance Are Modified by Haplotypes of the Glucocorticoid Receptor Gene J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4544 - 4551. [Abstract] [Full Text] [PDF]

				J. Majnik, A. Patocs, K. Balogh, M. Toth, P. Gergics, A. Szappanos, A. Mondok, G. Borgulya, P. Panczel, Z. Prohaszka, et al. Overrepresentation of the N363S Variant of the Glucocorticoid Receptor Gene in Patients with Bilateral Adrenal Incidentalomas J. Clin. Endocrinol. Metab., July 1, 2006; 91(7): 2796 - 2799. [Abstract] [Full Text] [PDF]

				A Luczay, D Torok, A Ferenczi, J Majnik, J Solyom, and G. Fekete Potential advantage of N363S glucocorticoid receptor polymorphism in 21-hydroxylase deficiency. Eur. J. Endocrinol., June 1, 2006; 154(6): 859 - 864. [Abstract] [Full Text] [PDF]

				J. A.E. Irving, L. Minto, S. Bailey, and A. G. Hall Loss of Heterozygosity and Somatic Mutations of the Glucocorticoid Receptor Gene Are Rarely Found at Relapse in Pediatric Acute Lymphoblastic Leukemia but May Occur in a Subpopulation Early in the Disease Course Cancer Res., November 1, 2005; 65(21): 9712 - 9718. [Abstract] [Full Text] [PDF]

				W. J.E. Tissing, J. P.P. Meijerink, M. L. den Boer, B. Brinkhof, E. F.C. van Rossum, E. R. van Wering, J. W. Koper, P. Sonneveld, and R. Pieters Genetic Variations in the Glucocorticoid Receptor Gene Are Not Related to Glucocorticoid Resistance in Childhood Acute Lymphoblastic Leukemia Clin. Cancer Res., August 15, 2005; 11(16): 6050 - 6056. [Abstract] [Full Text] [PDF]

				E. F. C. van Rossum, P. G. Voorhoeve, S. J. te Velde, J. W. Koper, H. A. Delemarre-van de Waal, H. C. G. Kemper, and S. W. J. Lamberts The ER22/23EK Polymorphism in the Glucocorticoid Receptor Gene Is Associated with a Beneficial Body Composition and Muscle Strength in Young Adults J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 4004 - 4009. [Abstract] [Full Text] [PDF]

				S. Wust, E. F. C. van Rossum, I. S. Federenko, J. W. Koper, R. Kumsta, and D. H. Hellhammer Common Polymorphisms in the Glucocorticoid Receptor Gene Are Associated with Adrenocortical Responses to Psychosocial Stress J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 565 - 573. [Abstract] [Full Text] [PDF]

				A. A. Syed, J. A. E. Irving, C. P. F. Redfern, A. G. Hall, N. C. Unwin, M. White, R. S. Bhopal, K. G. M. M. Alberti, and J. U. Weaver Low Prevalence of the N363S Polymorphism of the Glucocorticoid Receptor in South Asians Living in the United Kingdom J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 232 - 235. [Abstract] [Full Text] [PDF]

				E. F.C. van Rossum and S. W.J. Lamberts Polymorphisms in the Glucocorticoid Receptor Gene and Their Associations with Metabolic Parameters and Body Composition Recent Prog. Horm. Res., January 1, 2004; 59(1): 333 - 357. [Abstract] [Full Text]

				R. Rosmond, B. J. Morris, R. C.Y. Lin, and X. L. Wang Glucocorticoid Receptor Gene and Coronary Artery Disease: Right Idea, Wrong Gene Variant? * Response Hypertension, August 1, 2003; e4(2): . [Full Text] [PDF]

				R. C.Y. Lin, X. L. Wang, and B. J. Morris Association of Coronary Artery Disease With Glucocorticoid Receptor N363S Variant Hypertension, March 1, 2003; 41(3): 404 - 407. [Abstract] [Full Text] [PDF]

				M. R. Yudt and J. A. Cidlowski The Glucocorticoid Receptor: Coding a Diversity of Proteins and Responses through a Single Gene Mol. Endocrinol., August 1, 2002; 16(8): 1719 - 1726. [Abstract] [Full Text] [PDF]

				H. Esterbauer, H. Oberkofler, V. Linnemayr, B. Iglseder, M. Hedegger, P. Wolfsgruber, B. Paulweber, G. Fastner, F. Krempler, and W. Patsch Peroxisome Proliferator-Activated Receptor-{gamma} Coactivator-1 Gene Locus: Associations With Obesity Indices in Middle-Aged Women Diabetes, April 1, 2002; 51(4): 1281 - 1286. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dobson, M. G. Articles by Weaver, J. U. Search for Related Content PubMed PubMed Citation Articles by Dobson, M. G. Articles by Weaver, J. U.