Identification of marker genes for differential diagnosis of chronic fatigue syndrome

Department of General Medicine, Nagoya University Hospital, Nagoya, Japan.
Molecular Medicine (Impact Factor: 4.51). 08/2008; 14(9-10):599-607. DOI: 10.2119/2007-00059.Saiki
Source: PubMed


Chronic fatigue syndrome (CFS) is a clinically defined condition characterized by long-lasting disabling fatigue. Because of the unknown mechanism underlying this syndrome, there still is no specific biomarker for objective assessment of the pathological fatigue. We have compared gene expression profiles in peripheral blood between 11 drug-free patients with CFS and age- and sex-matched healthy subjects using a custom microarray carrying complementary DNA probes for 1,467 stress-responsive genes. We identified 12 genes whose mRNA levels were changed significantly in CFS patients. Of these 12 genes, quantitative real-time PCR validated the changes in 9 genes encoding granzyme in activated T or natural killer cells (GZMA), energy regulators (ATP5J2, COX5B, and DBI), proteasome subunits (PSMA3 and PSMA4), putative protein kinase c inhibitor (HINT ), GTPase (ARHC), and signal transducers and activators of transcription 5A (STAT5A). Next, we performed the same microarray analysis on 3 additional CFS patients and 20 other patients with the chief complaint of long-lasting fatigue related to other disorders (non-CFS patients) and found that the relative mRNA expression of 9 genes classified 79% (11/14) of CFS and 85% (17/20) of the non-CFS patients. Finally, real-time PCR measurements of the levels of the 9 involved mRNAs were done in another group of 18 CFS and 12 non-CFS patients. The expression pattern correctly classified 94% (17/18) of CFS and 92% (11/12) of non-CFS patients. Our results suggest that the defined gene cluster (9 genes) may be useful for detecting pathological responses in CFS patients and for differential diagnosis of this syndrome.

Download full-text


Available from: Nobutaro Ban, Aug 06, 2015
16 Reads
  • Source
    • "However, until now the role of viral infections as etiological agents for ME/CFS has been evaluated inconsistently [12] [13] [14] [15]. Identification of specific biomarkers for differential diagnosis of ME/CFS has intensively been studied [16] [17] [18] [19]. HHV-6 and HHV-7 are lymphotropic, neurotropic, and immunomodulating viruses which primary infection is followed by lifelong persistency. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Frequency of active human herpesvirus-6, -7 (HHV-6, HHV-7) and parvovirus B19 (B19) infection/coinfection and its association with clinical course of ME/CFS was evaluated. 108 ME/CFS patients and 90 practically healthy persons were enrolled in the study. Viral genomic sequences were detected by PCR, virus-specific antibodies and cytokine levels-by ELISA, HHV-6 variants-by restriction analysis. Active viral infection including concurrent infection was found in 64.8% (70/108) of patients and in 13.3% (12/90) of practically healthy persons. Increase in peripheral blood leukocyte DNA HHV-6 load as well as in proinflammatory cytokines' levels was detected in patients during active viral infection. Definite relationship was observed between active betaherpesvirus infection and subfebrility, lymphadenopathy and malaise after exertion, and between active B19 infection and multijoint pain. Neuropsychological disturbances were detected in all patients. The manifestation of symptoms was of more frequent occurrence in patients with concurrent infection. The high rate of active HHV-6, HHV-7 and B19 infection/coinfection with the simultaneous increase in plasma proinflammatory cytokines' level as well as the association between active viral infection and distinctive types of clinical symptoms shows necessity of simultaneous study of these viral infections for identification of possible subsets of ME/CFS.
    Advances in Virology 08/2012; 2012(12):205085. DOI:10.1155/2012/205085
  • Source
    • "Decreases in cytotoxic activity occur in CFS/ME and in some cases this is associated with differential expression in the levels of cytotoxic molecules [20,21,32,33]. These cytotoxic proteins and their genes including perforin (PRF1), granzyme A (GZMA), granzyme B (GZMB) and granzyme K (GZMK) have been shown to be either increased or decreased in CFS/ME [24,25,34]. For example, the perforin gene (PRF1) may increase in some cases of CFS/ME while intracellular perforin protein may be decreased in other CFS/ME patients [25]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is an etiologically unexplained disorder characterised by irregularities in various aspects of the immunological function. Presently, it is unknown whether these immunological changes remain consistent over time. This study investigates Natural Killer (NK) cell cytotoxic activity, NK cell subsets (CD56brightCD16- and CD56dimCD16+) and cytokines, over the course of a12 month period in patients with CFS/ME. The participants in the study comprised 65 (47.2 ± 11.5 years) CFS/ME participants and 21 (45.2 ±9.3 years) non-fatigued controls. Flow cytometry protocols were used to assess NK subsets and NK cytotoxic activity at various time points that included baseline (T1), 6 (T2) and 12 months (T3). Cytokine secretions were measured following mitogenic stimulation of peripheral blood mononuclear cells. NK cytotoxic activity was significantly decreased in the CFS/ME patients at T1, T2 and T3 compared to the non-fatigued group. Additionally, in comparison to the non-fatigued controls, the CFS/ME group had significantly lower numbers of CD56brightCD16- NK cells at both T1 and T2. Interestingly, following mitogenic stimulation, cytokine secretion revealed significant increases in IL-10, IFN-γ and TNF-α at T1 in the CFS/ME group. A significant decrease was observed at T2 in the CFS/ME group for IL-10 and IL-17A while at T3, IL-2 was increased in the CFS/ME group in comparison to the non-fatigued controls. Overall cytotoxic activity was significantly decreased at T3 compared to T1 and T2. CD56brightCD16- NK cells were much lower at T2 compared to T1 and T3. IL-10 and IL-17A secretion was elevated at T2 in comparison to T1 and T3. These results confirm decreases in immune function in CFS/ME patients, suggesting an increased susceptibility to viral and other infections. Furthermore, NK cytotoxic activity may be a suitable biomarker for diagnosing CFS/ME as it was consistently decreased during the course of the 12 months study.
    Journal of Translational Medicine 05/2012; 10(1):88. DOI:10.1186/1479-5876-10-88 · 3.93 Impact Factor
  • Source
    • "Consistent data worldwide suggest that a decrease in cytotoxic activity is a hallmark of CFS. In most cases this decrease has been associated with differential expression in cytotoxic molecules including GZMA, GZMK, GZMB and PRF1 (Brenu et al., 2011b; Saiki et al., 2008). "
    An International Perspective on the Future of Research in Chronic Fatigue Syndrome, 02/2012; , ISBN: 978-953-51-0072-0
Show more