Heterogenous circulating miRNA changes in ME/CFS converge on a unified cluster of target genes: A computational analysis, 2023, Kaczmarek

Abstract

Myalgic Encephalomyelitis / Chronic Fatigue Syndrome is a debilitating, multisystem disease of unknown mechanism, with a currently ongoing search for its endocrine mediators. Circulating microRNAs (miRNA) are a promising candidate for such a mediator and have been reported as significantly different in the patient population versus healthy controls by multiple studies. None of these studies, however, agree with each other on which specific miRNA are under- or over-expressed.

This discrepancy is the subject of the computational study presented here, in which a deep dive into the predicted gene targets and their functional interactions is conducted, revealing that the aberrant circulating miRNAs in ME/CFS, although different between patients, seem to mainly target the same specific set of genes (p ≈ 0.0018), which are very functionally related to each other (p ≲ 0.0001). Further analysis of these functional relations, based on directional pathway information, points to impairments in exercise hyperemia, angiogenic adaptations to hypoxia, antioxidant defenses, and TGF-β signaling, as well as a shift towards mitochondrial fission, corroborating and explaining previous direct observations in ME/CFS. Many transcription factors and epigenetic modulators are implicated as well, with currently uncertain downstream combinatory effects.

As the results show significant similarity to previous research on latent herpesvirus involvement in ME/CFS, the possibility of a herpesvirus origin of these miRNA changes is also explored through further computational analysis and literature review, showing that 8 out of the 10 most central miRNAs analyzed are known to be upregulated by various herpesviruses.

In total, the results establish an appreciable and possibly central role for circulating microRNAs in ME/CFS etiology that merits further experimental research.

Open access, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0296060

 

I'm not sure I'm understanding this correctly, but I think the hypothesis here is: A variety of circulating miRNAs are elevated in ME patients' blood, but overall these miRNAs inhibit a comparatively smaller set of genes, many of which are functionally related and could plausibly be connected to ME symptoms or results of previous studies. The variety of miRNAs may be due to different latent herpesviruses upregulating different miRNAs.

It seems like the implication of this is that we have a case of convergent evolution, where different herpesviruses are upregulating different miRNAs to target the same genes. Is that plausible though?

Alternatively, there's a lot of noise in these studies as the number of patients is relatively low and there is in fact a common set of upregulated miRNAs, we just can't see them yet. I wonder if anyone has tried to combine the data from these four studies to see what comes out?

 

Do the identified genes show any similarity to those highlighted by Precision Life' s genetic analysis ?

 

Quote from the paper:

"A sizable amount of the main findings from this analysis are consistent with experimental data in ME/CFS. Firstly, the most inhibited gene by far is VEGFA, coding for the Vascular Endothelial Growth Factor, a major secreted mediator of angiogenesis. Indeed VEGF-A levels in ME/CFS patients are decreased, as reported by Landi et al [24]. Gusnanto et al also found decreased VEGF-A as associated with ME/CFS status in a multivariate logistic regression analysis [25]"​

 

Of the 14 genes identified in Precision Life's ME/CFS paper, only PHACTR2 meets the threshold in this paper (associated with 5 circulating miRNAs). But I don't think we would expect overlap between these lists of genes, as the causality is running the opposite way (in Precision Life's analysis, the genes are associated with ME/CFS, so presumably causal in some way, while here the genes are being inhibited by circulating miRNAs).

 

Thanks

 

The author of this study posted on Phoenix Rising as user "necessary8". It would be a good opportunity for asking any questions should anyone have some.
https://forums.phoenixrising.me/thr...al-analysis-kaczmarek-2023.91330/post-2450554