We have previously reported the differential expression of 88 human genes in CFS/ME and evidence of clinically relevant subtypes.7 8
In the present study, we have confirmed this differential expression in 62 additional and previously untested CFS/ME patients. Combining the previous cohort and the new cohort, we have found evidence of eight genomic CFS/ME subtypes with marked differences in global functioning, clinical symptoms, levels of severity and geographical distribution. The function of these genes and their networks has been published previously.7
We have addressed the question of the specificity of these 88 genes to CFS/ME, by testing drug-free patients with endogenous depression. The fact that only five of these genes were abnormally expressed in these patients, as compared with normal controls, supports the view that CFS/ME and endogenous depression are biologically distinct, and that the psychological features of CFS/ME are in fact secondary to the pathogenesis.
It is particularly interesting that five of six CFS/ME patients with Q-CFS/ME clustered in the same subtype (subtype A). As these patients had had CFS/ME for several years, this finding suggests that they have a common underlying theme, which may be stable for a long time after the onset of disease. In view of this, and as various genes within this human gene signature are closely linked with EBV infection (NFKB1, EGR1, ETS1, GABPA, CREBBP, CXCR4, EBI2, HIF1A, JAK1, IL6R, IL7R, PIK3R1) and enterovirus infection (EIF4G1), we tested the serum samples for markers for four treatable microbial infections that are well recognised to trigger CFS/ME (EBV, enterovirus, parvovirus B19 and C burnetii (the agent of Q fever)) with the hypothesis that these genomic CFS/ME subtypes may represent host responses to particular infectious agents.
One patient with subtype E had acute parvovirus B19 at the time of sampling. This patient's symptoms were typical of CFS/ME, but this is not unexpected as parvovirus B19 is a recognised trigger for CFS/ME.13
The importance of testing for these infections is illustrated here, as we have shown previously that B19-CFS/ME is highly responsive to treatment with intravenous immunoglobulin.14
Six patients had acute enterovirus infections (of undetermined serotype) at the time of sampling, but there was no subtype relationship, as two patients were found to have each of subtypes A, E and G. Enteroviruses have long been recognised to trigger CFS/ME,15
and they have been detected in the stool16
and stomach epithelium17
in CFS/ME patients. Detection in the stomach has been shown to be associated with gastrointestinal symptoms in CFS/ME patients.17
However, in the present study, patients of subtypes A, E and G did not show gastrointestinal symptoms more often than the other patients.
Twelve CFS/ME patients and one normal subject had IgG to C burnetii phase II antigen, suggesting possible acute infection. Five of these CFS/ME patients were among those with Q-CFS/ME. The patients in whom these antibodies were detected had subtypes A, B, D, E and G. Therefore, apart from the patients with Q-CFS/ME (whose CFS/ME disease onset was associated with laboratory-documented acute Q fever), there were no subtype-specific relationships with C burnetii antibodies.
The subtype associations with EBV and EBV-linked genes are interesting, suggesting differences in the role of EBV and consequent host responses in the different subtypes. The finding of a noticeably large proportion of CFS/ME patients who were EBV seronegative (10%), compared with 4% in the normal group, was quite surprising given the strong link between EBV and CFS/ME. The fact that five of these 11 seronegative cases were subtype E is interesting, but remains unexplained at present.
It has been recognised for some time that subtypes of CFS/ME exist, and it has been thought that these subtypes may, at least in part, reflect particular aetiological factors.18
A symptom-based approach has had some success in identifying musculoskeletal, inflammatory and neurological subtypes19
; however, these groups had only minor differences in overall functional severity in contrast with those of the present study.
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 marked differences in the occurrence of particular symptoms and their severity. However, what precise sequence of events is involved in the genesis of the gene signatures in each subtype remains to be elucidated. Further work is required to validate and develop these findings.
- Expression of 88 human genes was confirmed as being significantly different between patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and normal controls.
- Gene expression in patients with endogenous depression was similar to that in normal controls.
- CFS/ME patients can be grouped into genomic subtypes which have different clinical phenotypes.
- There was evidence of subtype-specific relationships for Epstein–Barr virus and enterovirus, the two most common triggers for CFS/ME.