Glucocorticoid receptor polymorphisms and haplotypes associated with chronic fatigue syndrome

Abstract

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 hypothalamicpituitary-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 nonfatigued 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.

Selección supervisada de polimorfismos de nucleótido único en el síndrome de fatiga crónica

“…NR3C1 has been implicated as regulator of the hypothalamic-pituitary-adrenal axis (18) and of the immune function: the increase in its ligand affinity has led to a reduction in T cell numbers and to a change in susceptibility to Supervised SNP selection in chronic fatigue syndrome autoimmune diseases (19). A higher frequency of the NR3C1_11159943 major allele has also been reported in patients with chronic fatigue syndrome (20). Moreover, the model associated the syndrome with the minor allele of 5HTT_7911132, a SNP that belongs to a gene that decreases the level of active serotonin when the allelic variants with increased transcriptional activity are present (21).…”

Neuroendocrine disorder in chronic fatigue syndrome

“…This is supported by the different degree of fatigue in investigated patients and this theory rules in favor of genetic predisposition. On the other hand, immune reaction releases IL-6, which increases the quantity of free circulating cortisol by stimulating the hypothalamus CRH neurons and inhibiting the corticosteroid-building globulin gene (CBG) (26). All of this links CFS with possible hereditary disorders, including cortisol transport and CBG gene mutation as well as glucocorticoid resistance.…”

Pediatric Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…Variance in the expression of genes associated with HPA axis function has been found to be associated with ME/CFS [44][45][46]. For example, Rajeevan and colleagues [47] found that those with certain cortisol regulatory mechanisms (i.e., a single nucleotide polymorphism in the glucocorticoid receptor (GR) gene) were at increased risk for ME/CFS. Others have also found differences in the expression of glucocorticoid receptor NR3C1 in individuals with ME/CFS as compared to controls [33].…”