The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the funding agency.
Glucocorticoid receptor polymorphisms and haplotypes associated with chronic fatigue syndrome
Article first published online: 1 JUN 2006
No claim to original US government works
Genes, Brain and Behavior
Volume 6, Issue 2, pages 167–176, March 2007
How to Cite
Rajeevan, M. S., Smith, A. K., Dimulescu, I., Unger, E. R., Vernon, S. D., Heim, C. and Reeves, W. C. (2007), Glucocorticoid receptor polymorphisms and haplotypes associated with chronic fatigue syndrome. Genes, Brain and Behavior, 6: 167–176. doi: 10.1111/j.1601-183X.2006.00244.x
- Issue published online: 1 JUN 2006
- Article first published online: 1 JUN 2006
- Received 14 January 2006, revised 16 March 2006, accepted for publication 13 April 2006
- Chronic fatigue syndrome;
- glucocorticoid receptor gene (NR3C1);
- hypothalamic–pituitary–adrenal axis;
Chronic fatigue syndrome (CFS) is a significant public health problem of unknown etiology, the pathophysiology has not been elucidated, and there are no characteristic physical signs or laboratory abnormalities. Some studies have indicated an association of CFS with deregulation of immune functions and hypothalamic–pituitary–adrenal (HPA) axis activity. In this study, we examined the association of sequence variations in the glucocorticoid receptor gene (NR3C1) with CFS because NR3C1 is a major effector of the HPA axis. There were 137 study participants (40 with CFS, 55 with insufficient symptoms or fatigue, termed as ISF, and 42 non-fatigued controls) who were clinically evaluated and identified from the general population of Wichita, KS. Nine single nucleotide polymorphisms (SNPs) in NR3C1 were tested for association of polymorphisms and haplotypes with CFS. We observed an association of multiple SNPs with chronic fatigue compared to non-fatigued (NF) subjects (P < 0.05) and found similar associations with quantitative assessments of functional impairment (by the SF-36), with fatigue (by the Multidimensional Fatigue Inventory) and with symptoms (assessed by the Centers for Disease Control Symptom Inventory). Subjects homozygous for the major allele of all associated SNPs were at increased risk for CFS with odds ratios ranging from 2.61 (CI 1.05–6.45) to 3.00 (CI 1.12–8.05). Five SNPs, covering a region of approximately 80 kb, demonstrated high linkage disequilibrium (LD) in CFS, but LD gradually declined in ISF to NF subjects. Furthermore, haplotype analysis of the region in LD identified two associated haplotypes with opposite alleles: one protective and the other conferring risk of CFS. These results demonstrate NR3C1 as a potential mediator of chronic fatigue, and implicate variations in the 5′ region of NR3C1 as a possible mechanism through which the alterations in HPA axis regulation and behavioural characteristics of CFS may manifest.