Article

Integration of gene expression, clinical, and epidemiologic data to characterize Chronic Fatigue Syndrome

Viral Exanthems and Herpes Virus Branch, Division of Viral and Rickettsial Diseases, National Centre for Infectious Diseases, Centres for Disease Control and Prevention, 1600 Clifton Rd, Atlanta, Georgia.
Journal of Translational Medicine (Impact Factor: 3.99). 01/2004; 1(1):10. DOI: 10.1186/1479-5876-1-10
Source: PubMed

ABSTRACT Background
Chronic fatigue syndrome (CFS) has no diagnostic clinical signs or diagnostic laboratory abnormalities and it is unclear if it represents a single illness. The CFS research case definition recommends stratifying subjects by co-morbid conditions, fatigue level and duration, or functional impairment. But to date, this analysis approach has not yielded any further insight into CFS pathogenesis. This study used the integration of peripheral blood gene expression results with epidemiologic and clinical data to determine whether CFS is a single or heterogeneous illness.

Results
CFS subjects were grouped by several clinical and epidemiological variables thought to be important in defining the illness. Statistical tests and cluster analysis were used to distinguish CFS subjects and identify differentially expressed genes. These genes were identified only when CFS subjects were grouped according to illness onset and the majority of genes were involved in pathways of purine and pyrimidine metabolism, glycolysis, oxidative phosphorylation, and glucose metabolism.

Conclusion
These results provide a physiologic basis that suggests CFS is a heterogeneous illness. The differentially expressed genes imply fundamental metabolic perturbations that will be further investigated and illustrates the power of microarray technology for furthering our understanding CFS.

Download full-text

Full-text

Available from: Toni Whistler, Jul 26, 2015
0 Followers
 · 
105 Views
  • Source
    • "The heterogeneity of the patient population (Whistler et al., 2003) and the use of various methods and samples have contributed to conflicting results. Despite this various specific abnormalities have been observed repetitively in the ME/CFS patient population or substantial subgroup thereof (Table 2). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS) are used interchangeably, the diagnostic criteria define two distinct clinical entities. Cognitive impairment, (muscle) weakness, circulatory disturbances, marked variability of symptoms, and, above all, post-exertional malaise: a long-lasting increase of symptoms after a minor exertion, are distinctive symptoms of ME. This latter phenomenon separates ME, a neuro-immune illness, from chronic fatigue (syndrome), other disorders and deconditioning. The introduction of the label, but more importantly the diagnostic criteria for CFS have generated much confusion, mostly because chronic fatigue is a subjective and ambiguous notion. CFS was redefined in 1994 into unexplained (persistent or relapsing) chronic fatigue, accompanied by at least four out of eight symptoms, e.g., headaches and unrefreshing sleep. Most of the research into ME and/or CFS in the last decades was based upon the multivalent CFS criteria, which define a heterogeneous patient group. Due to the fact that fatigue and other symptoms are non-discriminative, subjective experiences, research has been hampered. Various authors have questioned the physiological nature of the symptoms and qualified ME/CFS as somatization. However, various typical symptoms can be assessed objectively using standardized methods. Despite subjective and unclear criteria and measures, research has observed specific abnormalities in ME/CFS repetitively, e.g., immunological abnormalities, oxidative and nitrosative stress, neurological anomalies, circulatory deficits and mitochondrial dysfunction. However, to improve future research standards and patient care, it is crucial that patients with post-exertional malaise (ME) and patients without this odd phenomenon are acknowledged as separate clinical entities that the diagnosis of ME and CFS in research and clinical practice is based upon accurate criteria and an objective assessment of characteristic symptoms, as much as possible that well-defined clinical and biological subgroups of ME and CFS patients are investigated in more detail, and that patients are monitored before, during and after interventions with objective measures and biomarkers.
    Frontiers in Physiology 03/2014; 5:109. DOI:10.3389/fphys.2014.00109 · 3.50 Impact Factor
  • Source
    • "The results indicate subtle changes in the immune system in CFS patients. Whistler et al (2003)* ‡ CFS 23/0 CDC By grouping the CFS patients according to the onset of illness (gradually/sudden), 117 genes differentially expressed in peripheral blood mononuclear cells were identified when using the Atlas Human 3.81 oligonucleotide glass microarrays containing 3800 genes. The majority of these genes were involved in oxidative phosphorylation, glucose metabolism, purine and pyrimidine metabolism, and glycolysis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Fatigue is a common symptom and includes both physical and mental components. It can be associated with a variety of different syndromes and diseases, but in many cases is not associated with other comorbid conditions. Most humans have experienced acute fatigue in relation to different stressors. Acute fatigue typically decreases as the effect of the triggering factor is reduced and a normal homeostatic balance is restored. Fatigue that persists for 6 months or more is termed chronic fatigue. Chronic fatigue (CF) in combination with a minimum of 4 of 8 symptoms and the absence of diseases that could explain these symptoms, constitute the case definition for chronic fatigue syndrome. In spite of its prevalence, the biology of fatigue is relatively poorly understood and biological markers have not yet been identified. This literature search was performed in PubMed to identify research on the genetics and epigenetics of fatigue. Publications were included if fatigue was a major topic and the topic was combined with genetic and/or epigenetic measurements in adult humans. A total of 40 publications were identified. Although altered functioning in the hypothalamic-pituitary-adrenal axis, the serotonergic system, and associations with infectious agents have been identified, the search for genetic or epigenetic markers of fatigue, either in the context of CF or chronic fatigue syndrome (CFS) has been relatively unproductive or, in the case of epigenetics, nonexistent. Although several studies, both hypothesis-testing and hypothesis-generating, have been performed to search for biomarkers, they have mostly been underpowered, restricted by the heterogeneity of the phenotype, or limited by an unsystematic study design. To be able to confirm the hypothesis that risk for, or levels of, fatigue are influenced by the genetic or epigenetic background of an individual, studies need to be based on larger sample sizes with a more clearly defined phenotype. Studies need to focus not only on the influence of a single aspect such as single nucleotide polymorphisms (SNPs) or differential gene expression on disease risk or state, but also on the systems biology behind the disease in combination with information on environmental influences and validation of findings in functional studies.
    PM&R 05/2010; 2(5):456-65. DOI:10.1016/j.pmrj.2010.04.003 · 1.66 Impact Factor
  • Source
    • "Contaminating deoxyribonucleic acid (DNA) was removed by incubation with 1 U DNaseI (GeneHunter Corp., TN) at 37 8C for 15 min. RNA was labeled and arrays processed as previously described (Ojaniemi et al., 2003; Whistler et al., 2003). Hybridization was onto a 20K array (MWG Biotech, Germany, now Ocimum Biosolutions). "
    [Show abstract] [Hide abstract]
    ABSTRACT: We investigated peripheral blood mononuclear cell gene expression responses to acute psychosocial stress to identify molecular pathways relevant to the stress response. Blood samples were obtained from 10 healthy male subjects before, during and after (at 0, 30, and 60 min) a standardized psychosocial laboratory stressor. Ribonucleic acid (RNA) was extracted and gene expression measured by hybridization to a 20,000-gene microarray. Gene Set Expression Comparisons (GSEC) using defined pathways were used for the analysis. Forty-nine pathways were significantly changed from baseline to immediately after the stressor (p<0.05), implicating cell cycle, cell signaling, adhesion and immune responses. The comparison between stress and recovery (measured 30 min later) identified 36 pathways, several involving stress-responsive signaling cascades and cellular defense mechanisms. These results have relevance for understanding molecular mechanisms of the physiological stress response, and might be used to further study adverse health outcomes of psychosocial stress.
    Biological psychology 08/2009; 82(2):125-32. DOI:10.1016/j.biopsycho.2009.06.009 · 3.47 Impact Factor
Show more