Treatment Avenues in ME/CFS: A Split-gender Pharmacogenomic Study of Gene-expression Modules., 2019, Jeffrey et al.



Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisymptom illness impacting up to 1 million people in the United States. As the pathogenesis and etiology of this complex condition are unclear, prospective treatments are limited. Identifying US Food and Drug Administration-approved drugs that may be repositioned as treatments for ME/CFS may offer a rapid and cost-effective solution.
Here we used gene-expression data from 33 patients with Fukuda-defined ME/CFS (23 females, 10 males) and 21 healthy demographically comparable controls (15 females, 6 males) to identify differential expression of predefined gene-module sets based on nonparametric statistics. Differentially expressed gene modules were then annotated via over-representation analysis using the Consensus Pathway database. Differentially expressed modules were then regressed onto measures of fatigue and cross-referenced with drug atlas and pharmacogenomics databases to identify putative treatment agents.
The top 1% of modules identified in males indicated small effect sizes in modules associated with immune regulation and mitochondrial dysfunction. In females, modules identified included those related to immune factors and cardiac/blood factors, returning effect sizes ranging from very small to intermediate (0.147 < Cohen δ < 0.532). Regression analysis indicated that B-cell receptors, T-cell receptors, tumor necrosis factor α, transforming growth factor β, and metabolic and cardiac modules were strongly correlated with multiple composite measures of fatigue. Cross-referencing identified genes with pharmacogenomics data indicated immunosuppressants as potential treatments of ME/CFS symptoms.
The findings from our analysis suggest that ME/CFS symptoms are perpetuated by immune dysregulation that may be approached via immune modulation-based treatment strategies.


"Deal with it"
Illinois, USA
I just found this article.

Interesting paragraphs (these are cut from various parts - not continuous):

Of note is that the presence of TGF-b modules has been associated with innate immune system activity as well as the maturation and differentiation of both innate and adaptive immune cells.54 It has been implicated in poor immunity in ME/CFS, which is supported by research showing higher levels in patients with ME/CFS.7,55e57 Unlike other biomarkers, TGF-b was the only biomarker elevated in a meta-analysis of data from ME/CFS studies.7

Additionally, in a study conducted by Trivedi et al,58 hypomethylation of a TGFBR1 promoter, implicating that the gene for the TGF-b receptor may be overexpressed. TGF-b elevation may be linked to “sickness behavior” or decreased motor activity, changes in energy intake, sleep abnormalities and cognitive deficits,59 as well as fatigue60 from immune system dysregulation.
In this work, we used gene-expression data from female and male patients with ME/CFS to identify druggable targets in differentially expressed genes from
predefined gene-pathway modules. Our results support the view that ME/CFS is a stress-mediated illness with underlying endocrine, immune, and mitochondrial imbalances accompanied by autonomic and physical dysfunction in both sexes.

Further analysis in the female cohort indicated that dysregulation of endocrine, immune, and metabolic function correlates strongly with ME/CFS symptomatology, and supports treatment strategies that would target both immune and endocrine hormone signaling pathways. These targetable pathways, especially TGF-b, pinpoint the immunologic dysfunction underlying ME/CFS presentation, and may also serve as potential biomarkers for this illness, as it has been shown to be consistently elevated across ME/CFS literature.7

Interestingly, the findings from this study also align with those from our previous investigation of altered neuroendocrine-immune homeostasis in ME/CFS using computational models of known immune, stress, and sex hormone signaling,69 and support the use of Th2 immunosuppressive agents targeting IL-4 and inhibition of glucocorticoid receptors, either individually or in conjunction.

In conclusion, this study supports established literature pointing toward immunologic
dysfunction, especially in TNF-a, while identifying potential targets for known pharmaceuticals to inform further research.