We read with interest the article by Mawdsley and Rampton on the relationship between psychological stress, increased disease activity in inflammatory bowel diseases (IBD), and the role of alterations in the hypothalamic‐pituitary‐adrenal (HPA) axis function (Gut 2005;54:1481–91). In IBD patients, chronic colonic inflammation induces downregulation of HPA axis responses, and animal studies have shown that altered function of the HPA axis renders rodents susceptible to stress induced increases in gastrointestinal inflammation. Central receptors located in the medial prefrontal cortex and hippocampus play a crucial role in glucocorticoid (GC) mediated counterregulation of stress induced HPA axis activation.1
Polymorphisms of the GC receptor (GR) gene may contribute to the large interindividual variations in sensitivity to GCs and HPA axis activity that are frequently observed in healthy individuals. Several polymorphisms of the GR gene have been described, and three of these are relatively frequent; however, knowledge of the influence of these polymorphisms on HPA axis response is very limited.
A genetic study was carried out in our laboratory to evaluate the incidence of these polymorphisms in 57 young patients with IBD (34 with Crohn's disease (CD) and 23 with ulcerative colitis (UC); mean age 13.8 years (range 1–45); 41.4% males, 58.6% females). The study was approved by the local ethics committee and written informed consent was obtained from all patients or their relatives or guardians. Studied polymorphisms have included BclI, in intron 2, and the N363S polymorphism in exon 2, that have been associated with an increased sensitivity to GCs in vivo,2,3 and the ER22/23EK polymorphism, in exon 2, associated with a partial form of GC resistance.4 Genomic DNA was extracted from peripheral leucocytes, amplified with specific primers, and subsequently digested with MnlI (ER22/23EK), Tsp509I (N363S), or BclI restriction enzymes.5,6
The results of the analysis are presented in table 1. We found a significantly higher frequency of the BclI mutated genotype in patients with CD compared with healthy controls (p = 0.03, Fisher test; odds ratio 3.84 (95% confidence interval 1.23–11.91)). In contrast, no difference was observed between UC patients and controls.
Table 1 BclI, ER22/23EK, and N363S genotype in patients with Crohn's disease (CD), ulcerative colitis (UC), and controls.
| Genotype (n (%)) | OR (95% CI) | ||||
|---|---|---|---|---|---|
| Wild‐type | Heterozygous | Mutated | Mutated v not mutated | p Value | |
| BclI | |||||
| Controls (n = 70) | 30 (42.9%) | 34 (48.5%) | 6 (8.6%) | – | – |
| CD (n = 34) | 9 (26.5%) | 16 (47%) | 9 (26.5%) | 3.84 (1.23–11.91) | 0.03 |
| UC (n = 23) | 10 (43.5%) | 12 (52.2%) | 1 (4.3%) | 1.03 (0.39–2.65) | 1 |
| ER22/23EK | Wild‐type | Heterozygous | Mutated | Heterozygous v wild‐type | |
| Controls (n = 70) | 67 (95.7%) | 3 (4.3%) | 0 (0%) | – | – |
| CD (n = 34) | 32 (94.1%) | 2 (5.9%) | 0 (0%) | 1.39 (0.22–8.78) | 0.6 |
| UC (n = 23) | 22 (95.7%) | 1 (4.3%) | 0 (0%) | 1.01 (0.10–10.27) | 1 |
| N363S | Wild‐type | Heterozygous | Mutated | Heterozygous v wild‐type | |
| Controls (n = 70) | 67 (95.7%) | 3 (4.3%) | 0 (0%) | – | – |
| CD (n = 34) | 33 (97.1%) | 1 (2.9%) | 0 (0%) | 0.68 (0.07–6.76) | 1 |
| UC (n = 23) | 21 (91.3%) | 2 (8.7%) | 0 (0%) | 2.13(0.33–13.60) | 0.6 |
OR (95% CI), odds ratio (95% confidence interval).
The BclI polymorphism has been associated with high systolic pressure, insulin sensitivity, body mass index, and abdominal fat distribution2,7; carriers of the mutated allele have increased GC sensitivity and higher cortisol suppression after low dose dexamethasone.8 A higher frequency of the mutated genotype was observed in this study in patients with CD; this mutation could lead to increased sensitivity in peripheral and central GRs, determining a raised susceptibility to feedback inhibition of GCs on the HPA axis. It is of interest that previous studies have demonstrated,9 in a subgroup of patients with CD, alterations of the HPA axis resulting in relative hypocortisolism.
In contrast, no difference was observed for the N363S polymorphism, associated with increased sensitivity to GCs,3,10 or for the ER22/23EK polymorphism, associated with a partial form of GC resistance (table 1).4
This is the first study to examine the possibility that IBD may be associated with GR polymorphisms; our results support the hypothesis that common polymorphisms in the GR gene may have modulating effects on the relation between psychological factors and HPA axis regulation in patients with CD. However, these data need to be confirmed in a larger group of patients.
Acknowledgements
This research was supported by grants from the Italian Ministry of University and Scientific Research (PRIN projects 2004065777 and 2003053403) and the Italian Ministry of Health. Dr Sara De Iudicibus, Dr Gabriele Stocco, and Dr Ilenia Drigo are recipients of research fellowships from IRCCS Burlo Garofolo, Trieste.
Footnotes
Conflict of interest: None declared.
References
- 1.Sternberg E M, Chrousos G P, Wilder R L.et al The stress response and the regulation of inflammatory disease. Ann Intern Med 1992117854–866. [DOI] [PubMed] [Google Scholar]
- 2.Buemann B, Vohl M C, Chagnon M.et al Abdominal visceral fat is associated with a BclI restriction fragment length polymorphism at the glucocorticoid receptor gene locus. Obes Res 19975186–192. [DOI] [PubMed] [Google Scholar]
- 3.Lin R C, Wang W Y, Morris B J. High penetrance, overweight, and glucocorticoid receptor variant: case‐control study. BMJ 19993191337–1338. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.van Rossum E F, Koper J W, Huizenga N A.et al A polymorphism in the glucocorticoid receptor gene, which decreases sensitivity to glucocorticoids in vivo, is associated with low insulin and cholesterol levels. Diabetes 2002513128–3134. [DOI] [PubMed] [Google Scholar]
- 5.Koper J W, Stolk R P, de Lange P.et al Lack of association between five polymorphisms in the human glucocorticoid receptor gene and glucocorticoid resistance. Hum Genet 199799663–668. [DOI] [PubMed] [Google Scholar]
- 6.Bachmann A W, Sedgley T L, Jackson R V.et al Glucocorticoid receptor polymorphisms and post‐traumatic stress disorder. Psychoneuroendocrinology 200530297–306. [DOI] [PubMed] [Google Scholar]
- 7.Weaver J U, Hitman G A, Kopelman P G. An association between a Bc1I restriction fragment length polymorphism of the glucocorticoid receptor locus and hyperinsulinaemia in obese women. J Mol Endocrinol 19929295–300. [DOI] [PubMed] [Google Scholar]
- 8.van Rossum E F, Koper J W, van den Beld A W.et al Identification of the BclI polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids in vivo and body mass index. Clin Endocrinol 200359585–592. [DOI] [PubMed] [Google Scholar]
- 9.Reinshagen M, Haefele T, Holicki S.et al The ultra low dose ACTH‐test identifies a subgroup of patients with Crohn's disease and an impaired hypothalamo‐pituitary‐adrenal (HPA) axis. Gastroenterology 2002122S1384 [Google Scholar]
- 10.Huizenga N A, Koper J W, De Lange P.et al A polymorphism in the glucocorticoid receptor gene may be associated with increased sensitivity to glucocorticoids in vivo. J Clin Endocrinol Metab 199883144–151. [DOI] [PubMed] [Google Scholar]