NEW Kerr Article on Gene Expression Subtypes (published 4/15/08)

Discussion in 'Fibromyalgia Main Forum' started by mezombie, May 18, 2008.

  1. mezombie

    mezombie Member

    Gene Expression Subtypes in Patients with
    Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

    Journal: J Infect Dis. 2008 Apr 15;197(8):1171-1184.

    Authors: Kerr JR, Petty R, Burke B, Gough J, Fear D, Sinclair LI, Mattey DL, Richards SC, Montgomery J, Baldwin DA, Kellam P, Harrison TJ, Griffin GE, Main J, Enlander D, Nutt DJ, Holgate ST.

    NLM Citation: PMID: 18462164


    Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a multisystem disease, the pathogenesis of which remains undetermined.

    We set out to determine the precise abnormalities of gene expression in the blood of patients with CFS/ME. We analyzed gene expression in peripheral blood from 25 patients with CFS/ME diagnosed according to the Centers for Disease Control and Prevention diagnostic criteria and 50 healthy blood donors, using a microarray with a cutoff fold difference of expression of >/=2.5. Genes showing
    differential expression were further analyzed in 55 patients with CFS/ME and 75 healthy blood donors, using quantitative polymerase chain reaction.

    Differential expression was confirmed for 88 genes; 85 were upregulated, and 3 were downregulated. Highly represented functions were hematological disease and function, immunological disease and function, cancer, cell death, immune response, and infection. Clustering of quantitative polymerase chain reaction data from patients with CFS/ME revealed 7 subtypes with distinct differences in Medical Outcomes Survey Short Form-36 scores, clinical
    phenotypes, and severity.


    In this article, we document the differential expression of 88 human genes in CFS/ME. We have confirmed involvement of all 16 genes reported in our pilot study [13] in the same direction as previously reported, except IL10RA, which was downregulated in the previous study [13] but upregulated in the present study. This discrepancy remains unexplained, but because IL10RA is a critical gene required for T cell activation and since IL10RA levels correlate with measures of general health, we believe it to be particularly important.

    The functions of these genes present a complex picture with links to several diseases and pathways (tables 35). Prominent themes that are well recognized in patients with CFS/ME are immunity, inflammation, and infection [5, 13]; cell death [13, 24]; cancer [25, 26]; and neurological disease [13, 2729].

    One of the most important viral triggers of CFS/ME is EBV, and this virus very likely plays an important role in perpetuation of disease, because it is reactivated by stress [30]. Within the gene signature identified in this study, the following 12 human genes that we found to be upregulated in patients with CFS/ME have been shown elsewhere to be upregulated, either directly or indirectly, by EBV infection: NFKB1, EGR1, ETS1, GABPA, CREBBP, CXCR4, and EBI2 [31]; HIF1A; JAK1; IL6R; IL7R; and PIK3R1. A particularly interesting gene is EBI2, which was upregulated in 55% of patients with CFS/ME, one of whom was a 26-year-old woman with CFS/ME triggered by laboratory documented EBV infection 10 years earlier. The EBV genes BRLF1 and BZLF1 mediate the switch from latent to lytic phases of EBV infection, and during this process they transactivate many human genes. It is interesting that BRLF1 was identified as being overrepresented in the transcription factor analysis and that IgG specific to the Zebra protein (the BZLF1 gene product) has been reported
    previously in patients with CFS/ME [32].

    Enteroviruses are another very important viral trigger of CFS/ME [33]. Upregulation of EIF4G1 transcript variant 5, which was found in this study and elsewhere [8, 13], is targeted during infection by various viruses, including enteroviruses, to subvert cellular machinery for the production of viral proteins.

    The theme of neurological disease and function was prominent among the 88 CFS/ME-associated genes, almost all of which are expressed in multiple areas of the human brain (data not shown). Involvement of specific genes highlights the importance of neuregulin signaling, neurotrophin/TRK signaling, axonal guidance signaling, dopamine receptor signaling, and Huntington disease signaling (table 5). NTE was upregulated in blood of patients with CFS/ME, both in this study and our pilot study [13]. NTE is the primary site of action of organophosphate (OP) compounds, such as sarin, which cause axonal degeneration and paralysis due to inactivation of its serine esterase activity [34]. In the nervous system
    of adult chickens, OP-modified NTE initiates neurodegeneration. NTE probably regulates neuron-glial interactions during development and possibly also during adult life [35]. Exposure to OPs may trigger CFS/ME [36] and Gulf War illness [37]. Furthermore, the heterogeneity of NTE levels seen in patients with CFS/ME is consistent with a role for OPs in only a subset of patients with CFS/ME. In this study, 3 of 28 patients with CFS/ME for whom NTE data passed quality control analysis had high NTE
    levels, compared with uniformly low levels in healthy blood donors. This is in contrast to data from our pilot study, in which 10 of 17 patients with CFS/ME showed high NTE levels [13]. The discrepancy between the studies is interesting, given that in our pilot study all patients with individual PCR results for NTE were from Dorset, whereas in the present study 11 patients were from Dorset; 1 was from Leicester, United Kingdom; 5 were from Bristol; 5 were from London; and 6 were from New York.

    Another interesting gene that affects neurological function is EIF2B4, mutations within which are associated with vanishing white matter disease [38]. This is interesting in view of the white matter hyperintensity lesions that have been documented in patients with CFS/ME [2729].

    We have identified involvement of several genes of the interleukin-6 (IL-6) signaling pathway, consistent with the findings of several previous studies [39, 40]. Although we found upregulation of the genes encoding IL-6R and IL-6ST, the 2 IL-6 receptors, we did not find evidence for upregulation of the gene encoding IL-6 itself, which may explain the inconsistent findings by different groups in this area.

    It is intriguing that it is possible to identify CFS/ME
    subtypes on the basis of expression values for these 88 genes and even more so that these subtypes have distinct clinical phenotypes, with such marked differences in the occurrence of particular symptoms and their severity. It has been recognized for some time that subtypes of CFS/ME exist, and it has been thought that these subtypes may, at least in part, reflect particular etiological factors [41]. A symptom-based approach has had some success in
    identifying musculoskeletal, inflammatory, and neurological subtypes [42]; however, these groups had only minor differences between them in overall functional severity, in contrast to the subtypes in the present study. A more detailed analysis of clinical and molecular features of these subtypes will be presented in a separate article. Further work is urgently required to validate and develop these findings.

    [This Message was Edited on 05/18/2008]
  2. Khalyal

    Khalyal New Member

    Important information. Thanks for posting it for us!

  3. Elisa

    Elisa Member

    Thanks for posting.

    This is really going to crack the code, IMHO.

    I think we should encourage those that are able to send support to his foundation. And e-mails of gratitude.

    This feels like it may lead to some important developments/treatments for all of us.

    I think we should pray for Dr Kerr and all CFS/FM researchers...

    God Bless,

    [This Message was Edited on 05/18/2008]
  4. Marta608

    Marta608 Member

    Interesting information!

  5. aftermath

    aftermath New Member

    Are doing some great work over there across the pond.

    The only thing I don't like are the statements I have seen attributed to him regarding the possibility of a cure within 1-2 years. You don't have this kind of optimism out of any of the other top research camps.

    I just get concerned that he is getting people's hopes up for nothing.
  6. mezombie

    mezombie Member

    I do think this is promising research.
  7. ian58

    ian58 New Member

    There is a conference in the UK on 23rd May 2008 and Dr Kerr is speaking at it so maybe we will learn more then.
    [This Message was Edited on 05/19/2008]
  8. simpsons

    simpsons Member

    I recieved this paper from co-cure, i was very interested in the following part

    Analysis of mean age and sex ratios for each subtype revealed that subtypes
    3, 5, and 7 occurred only in females, subtype 2 was predominantly male, and
    the remaining subtypes occurred in both males and females; age differences
    were less clearly demarcated. The clinical phenotype was distinct between
    subtypes; subtypes 1 and 7 were the most severe, followed sequentially by
    subtypes 2, 4, 5, 6, and 3.

    interesting that the illness can be different between the sex's sub group wise.

  9. mezombie

    mezombie Member

    I didn't want to post the entire article because of its length. As posted above, it is available at Co-Cure.

    If you want to read the entire article, go to:

    Click on "Articles and Posts" in the left hand margin

    Click on "Research Posts"

    The article is at post 019193.

    References, tables, etc. are posted separately from post 019193 through 019199.
  10. Lichu3

    Lichu3 New Member

    Hopefully the work of Lerner/Montoya/Glaser (all dealing with EBV and CFS) coalesces with that of Kerr. Also, I hope Kerr and Baranuik (Georgetown guy studying unusual proteins in spinal fluid of people with CFS) talk to each other. Maybe the proteins he's seeing are the products of the mRNAs Kerr is seeing.
  11. marti_zavala

    marti_zavala Member

    I think they are at least watching each others work.

    "Dr. Kerr then noted several intersections between his gene expression results and other findings. Both that his gene expression and Dr. Baraniuk’s cerebral spinal fluid proteome results have highlighted gelsolin - a possible marker of amyloidosis. Likewise the Nestad study suggested that mitochondrial problems caused the increased lactate brain levels found. "

    Good news but we are still a long way's off.
  12. Jayna

    Jayna New Member

    And our brains' white matter is still clogging up (or whatever) with every passing day.

    I only hope they figure out the brain stuff before my head is completely empty (although, if you asked my family some days... LOL)
  13. Mikie

    Mikie Moderator

    This is amazing info and I am surprised that this much progress has been achieved in determining genetic mutations and subtypes. Regardless of when a cure comes, if this much has already been achieved, there is likely to be more research which gives our illnesses greater importance.

    Thanks again.

    Love, Mikie
  14. foxglove9922

    foxglove9922 New Member

    My daugther and I are 2 of PWC who were part of this study. We will find out which subset we fell into this week and hopefully will begin a new protocol based on this information.

    Will keep everyone posted as soon as I know more.