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 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.

 

Source: Rajeevan MS, Smith AK, Dimulescu I, Unger ER, Vernon SD, Heim C, Reeves WC. Glucocorticoid receptor polymorphisms and haplotypes associated with chronic fatigue syndrome. Genes Brain Behav. 2007 Mar;6(2):167-76. http://onlinelibrary.wiley.com/doi/10.1111/j.1601-183X.2006.00244.x/full (Full article)

 

Reduced levels of oestrogen receptor beta mRNA in Swedish patients with chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is an illness with unknown aetiology and pathophysiology. The difference in incidence by sex observed for CFS indicates a role for oestrogen and oestrogen receptors in disease development. Furthermore, an immunomediated pathogenesis has been suggested for CFS, providing an additional connection to oestrogen, which displays immunomodular functions.

AIMS: To investigate a possible association of oestrogen receptor (ER) mRNAs and two ERbeta single-nucleotide polymorphisms (SNPs) with CFS.

METHODS: Messenger RNA levels of ERalpha, ERbeta wt and ERbeta cx were investigated in peripheral blood mononuclear cells from 30 patients with CFS and 36 healthy controls by quantitative real-time polymerase chain reaction. Two ERbeta SNPs were scored in the same material.

RESULTS: The CFS group showed significantly lower mRNA expression levels of ERbeta wt compared with the healthy control group. No differences were observed for ERalpha or ERbeta cx between patients and controls. There were no significant differences in frequency for the investigated ERbeta SNPs between cases and controls.

CONCLUSIONS: The reduced ERbeta wt expression level observed in this study is consistent with an immune-mediated pathogenesis of CFS. Additionally, the observation that ERbeta wt expression is decreased in CFS could provide an entry point to identify interesting, potentially disease-causing, candidate molecules for further study. A possible connection between oestrogen, oestrogen receptors and CFS should be evaluated further.

 

Source: Gräns H, Nilsson M, Dahlman-Wright K, Evengård B. Reduced levels of oestrogen receptor beta mRNA in Swedish patients with chronic fatigue syndrome. J Clin Pathol. 2007 Feb;60(2):195-8. Epub 2006 May 26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1860629/

 

Coping styles in people with chronic fatigue syndrome identified from the general population of Wichita, KS

Abstract:

OBJECTIVE: Studies of primary and tertiary care patients suggest that maladaptive coping styles contribute to the pathogenesis and maintenance of chronic fatigue syndrome (CFS). We assessed coping styles in persons with unexplained fatigue and nonfatigued controls in a population-based study.

METHODS: We enrolled 43 subjects meeting the 1994 Research Case Definition of CFS, matching them with 61 subjects with chronic unexplained fatigue who did not meet criteria for CFS [we term them insufficient symptoms or fatigue (ISF)] and 60 non-ill (NI) controls. Coping styles and clinical features of CFS were assessed using standard rating scales.

RESULTS: Subjects with CFS and ISF reported significantly more escape-avoiding behavior than NI controls. There were no differences between the CFS and ISF subjects. Among participants with CFS, escape-avoiding behavior was associated with fatigue severity, pain, and disability.

CONCLUSIONS: We demonstrate significantly higher reporting of maladaptive coping in a population-based sample of people with CFS and other unexplained fatiguing illnesses defined by reproducible standardized clinical empirical means in comparison to NI controls.

 

Source: Nater UM, Wagner D, Solomon L, Jones JF, Unger ER, Papanicolaou DA, Reeves WC, Heim C. Coping styles in people with chronic fatigue syndrome identified from the general population of Wichita, KS. J Psychosom Res. 2006 Jun;60(6):567-73. https://www.ncbi.nlm.nih.gov/pubmed/16731231

 

Impaired natural immunity, cognitive dysfunction, and physical symptoms in patients with chronic fatigue syndrome: preliminary evidence for a subgroup?

Abstract:

OBJECTIVE: The diagnostic criteria of chronic fatigue syndrome (CFS) define a heterogeneous population composed of several subgroups. Past efforts to identify subgroup markers have met with mixed success. This study was designed to examine natural killer cell activity (NKCA) as a potential subgroup marker by comparing the clinical presentations of CFS patients with and without clinically reduced NKCA.

METHODS: Forty-one female CFS patients were classified into having either low or normal NKCA levels. These subgroups were then compared on objective measures of cognitive functioning and subjective assessments of fatigue, vigor, cognitive impairment, and daytime dysfunction.

RESULTS: Relative to CFS patients in the normal-NKCA subgroup, low-NKCA patients reported less vigor, more daytime dysfunction, and more cognitive impairment. In addition, low-NKCA patients performed less on objective measures of cognitive functioning relative to normal-NKCA patients.

CONCLUSIONS: The results are offered as preliminary evidence in support of using NKCA as an immunological subgroup marker in CFS. Findings are also discussed in terms of known associations between dysregulated immune functions, somatic symptoms, and psychological stress.

 

Source: Siegel SD, Antoni MH, Fletcher MA, Maher K, Segota MC, Klimas N. Impaired natural immunity, cognitive dysfunction, and physical symptoms in patients with chronic fatigue syndrome: preliminary evidence for a subgroup? J Psychosom Res. 2006 Jun;60(6):559-66. https://www.ncbi.nlm.nih.gov/pubmed/16731230

 

Spectroscopic diagnosis of chronic fatigue syndrome by visible and near-infrared spectroscopy in serum samples

Abstract:

To investigate visible and near-infrared (Vis-NIR) spectroscopy enabling chronic fatigue syndrome (CFS) diagnosis, we subjected sera from CFS patients as well as healthy donors to Vis-NIR spectroscopy. Vis-NIR spectra in the 600-1100 nm region for sera from 77 CFS patients and 71 healthy donors were subjected to principal component analysis (PCA) and soft independent modeling of class analogy (SIMCA) to develop multivariate models to discriminate between CFS patients and healthy donors. The model was further assessed by the prediction of 99 masked other determinations (54 in the healthy group and 45 in the CFS patient group).

The PCA model predicted successful discrimination of the masked samples. The SIMCA model predicted 54 of 54 (100%) healthy donors and 42 of 45 (93.3%) CFS patients of Vis-NIR spectra from masked serum samples correctly. These results suggest that Vis-NIR spectroscopy for sera combined with chemometrics analysis could provide a promising tool to objectively diagnose CFS.

 

Source: Sakudo A, Kuratsune H, Kobayashi T, Tajima S, Watanabe Y, Ikuta K. Spectroscopic diagnosis of chronic fatigue syndrome by visible and near-infrared spectroscopy in serum samples. Biochem Biophys Res Commun. 2006 Jul 14;345(4):1513-6. Epub 2006 May 22. https://www.ncbi.nlm.nih.gov/pubmed/16730652

 

Chronic fatigue syndrome-like caseness as a predictor of work status in fatigued employees on sick leave: four year follow up study

Abstract:

OBJECTIVE: To assess whether CFS-like caseness (meeting the criteria for chronic fatigue syndrome (CFS)) predicts work status in the long term.

METHODS: Prospective study in a sample of fatigued employees absent from work. Data were collected at baseline and four years later, and included CFS-like caseness and work status (inactive work status and full work incapacity).

RESULTS: CFS-like cases at baseline were three times more likely to be unable to work at follow up than fatigued employees who did not meet CFS criteria at baseline (ORs 3-3.3). These associations grew even stronger when demographic and clinical confounders were controlled for (ORs 3.4-4.4).

CONCLUSION: A CFS-like status (compared to non-CFS fatigue) proved to be a strong predictor of an inactive work status and full work incapacity in the long term. Since little is known about effective interventions that prevent absenteeism and work incapacity or facilitate return to work in subjects with chronic fatigue, there is a great need for powerful early interventions that restore or preserve the ability to work, especially for workers who meet criteria for CFS.

 

Source: Huibers MJ, Leone SS, Kant IJ, Knottnerus JA. Chronic fatigue syndrome-like caseness as a predictor of work status in fatigued employees on sick leave: four year follow up study. Occup Environ Med. 2006 Aug;63(8):570-2. Epub 2006 May 12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2078121/ (Full article)

 

GMC must consider case against paediatricians who suspected parents of fabricating child’s illness

A couple suspected of fabricating their daughter’s illness and threatened with having her taken into care have won a High Court ruling that the General Medical Council must reconsider their complaint against the two paediatricians who raised the concerns.

The girl, now 15 years old, was eventually diagnosed with chronic fatigue syndrome. The local council agreed to withdraw the care proceedings and was ordered to pay the family’s costs after an independent expert appointed by the court and the doctor treating the girl made the diagnosis.

Her father, named only as Mr F to protect his daughter’s identity, lodged a complaint with the GMC against the paediatricians, who were named in the High Court judgment as Dr A and Dr B.

Mr F’s complaint included an allegation that the doctors had changed their minds and accepted that chronic fatigue syndrome was the correct diagnosis but had not immediately informed the local authority or the court hearing the case.

The charges were drawn up and the case went to the GMC’s preliminary proceedings committee (PPC), but, in July 2004, that committee decided not to refer the case to the professional conduct committee and threw it out.

Mr F sought a judicial review, arguing that the allegations were sufficient, if proved, to support a finding of serious professional misconduct. The GMC was willing to send the case back to the PPC, but the two doctors intervened as interested parties to oppose the application.

Mr Justice Sullivan ruled that the committee had failed to deal with the allegations and should have made further inquiries. He said that the charges as formulated had raised a specific allegation that the doctors had engaged in deceitful conduct, which had to be dealt with in the committee’s reasoning, and sent the case back to the committee.

A spokesman for the GMC said, “We note the decision handed down by Mr Justice Sullivan. The case will be referred back to the PPC for consideration.”

You can read the rest of this article here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1459583/

Source: Dyer C. GMC must consider case against paediatricians who suspected parents of fabricating child’s illness. BMJ. 2006 May 13;332(7550):1110. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1459583/ (Full article)

Chronic fatigue syndrome: an update focusing on phenomenology and pathophysiology

Abstract:

PURPOSE OF REVIEW: Chronic fatigue syndrome is a controversial condition especially concerning its clinical definition and aetiopathogenesis. Most recent research progress has been made in phenomenology and pathophysiology and we focused our review on these two areas.

RECENT FINDINGS: The phenomenology research supports the notion of a discrete fatigue syndrome which can be distinguished from depression and anxiety. The current case definition, however, may need an improvement based on empirical data. Recent advances in understanding the pathophysiology of chronic fatigue syndrome continue to demonstrate the involvement of the central nervous system. Hyperserotonergic state and hypoactivity of the hypothalamic-pituitary-adrenal axis constitute other findings, but the question of whether these alterations are a cause or consequence of chronic fatigue syndrome still remains unanswered. Immune system involvement in the pathogenesis seems certain but the findings on the specific mechanisms are still inconsistent. Genetic studies provide some evidence of the syndrome being a partly genetic condition, but environmental effects seem to be still predominant and identification of specific genes is still at a very early stage.

SUMMARY: The recent findings suggest that further research is needed in improving the current case definition; investigating overlaps and boundaries among various functional somatic syndromes; answering the question of whether the pathophysiologic findings are a cause or consequence; and elucidating the involvement of the central nervous system, immune system and genetic factors.

 

Source: Cho HJ, Skowera A, Cleare A, Wessely S. Chronic fatigue syndrome: an update focusing on phenomenology and pathophysiology. Curr Opin Psychiatry. 2006 Jan;19(1):67-73. https://www.ncbi.nlm.nih.gov/pubmed/16612182

 

Clinical methodology and its implications for the study of therapeutic interventions for chronic fatigue syndrome: a commentary

Abstract:

Chronic fatigue syndrome (CFS) is a complex, multisymptom illness of unknown etiology. A variety of operational case definitions based on symptom report have been developed that share some common clinical features. Patients often come to clinical presentation after months or, more typically, years of symptomatic distress. Comorbid presentation with psychiatric illnesses has been noted.

Due to these fundamental issues, the impact of patient selection and the specification of the methods of outcome assessment loom large in therapeutic studies of CFS. While a substantial body of research has focused on increasing our understanding of the basic pathobiology of CFS, there have been comparatively fewer studies that have addressed the problems of patient characterization and outcome assessment. The role of clinical methodology in the study of the therapeutics of CFS is not trivial, and may confound our understanding of pragmatic recommendations for treatment.

 

Source: Demitrack MA. Clinical methodology and its implications for the study of therapeutic interventions for chronic fatigue syndrome: a commentary. Pharmacogenomics. 2006 Apr;7(3):521-8. https://www.ncbi.nlm.nih.gov/pubmed/16610962

 

Interpreter of maladies: redescription mining applied to biomedical data analysis

Abstract:

Comprehensive, systematic and integrated data-centric statistical approaches to disease modeling can provide powerful frameworks for understanding disease etiology. Here, one such computational framework based on redescription mining in both its incarnations, static and dynamic, is discussed.

The static framework provides bioinformatic tools applicable to multifaceted datasets, containing genetic, transcriptomic, proteomic, and clinical data for diseased patients and normal subjects. The dynamic redescription framework provides systems biology tools to model complex sets of regulatory, metabolic and signaling pathways in the initiation and progression of a disease.

As an example, the case of chronic fatigue syndrome (CFS) is considered, which has so far remained intractable and unpredictable in its etiology and nosology. The redescription mining approaches can be applied to the Centers for Disease Control and Prevention’s Wichita (KS, USA) dataset, integrating transcriptomic, epidemiological and clinical data, and can also be used to study how pathways in the hypothalamic-pituitary-adrenal axis affect CFS patients.

 

Source: Waltman P, Pearlman A, Mishra B. Interpreter of maladies: redescription mining applied to biomedical data analysis. Pharmacogenomics. 2006 Apr;7(3):503-9. https://www.ncbi.nlm.nih.gov/pubmed/16610960