Preprint Charting the Circulating Proteome in ME/CFS: Cross System Profiling and Mechanistic insights, 2025, Hoel, Fluge, Mella+

The patients are from RituxME and CycloME. Age and gender matched controls.

 

54 ME/CFS and 27 HC.

6494 proteins tested. 751 with significant q values.

Down: intracellular proteins, including histones, metabolic enzymes | Up: immune system, metabolism | Up or down: vascular function

Controlling for metabotype (what is metabotype?) and SF-36 physical function score to try to control for physical activity.

Reduction in granulocyte associated proteins. 40% of neutrophil associated proteins were decreased. (Does this mean significantly decreased? How many were significantly increased?)

I don't know what Ephrin is, but they said it's interesting so maybe it's interesting.

29 is Germain, A., Levine, S.M., and Hanson, M.R. (2021). In-Depth Analysis of the Plasma Proteome in ME/CFS Exposes Disrupted Ephrin-Eph and Immune System Signaling. Proteomes 9, 6. https://10.3390/proteomes9010006 S4ME

They followed up this aptamer-based protein measurement method on a smaller set of proteins using an antibody-based method. It appears to be on different participants as well.

Is the 212 and 66 the total number of people in the ME/CFS biobank, while 83 and 48 are the number they chose for the validation portion? It says they randomly selected participants for both stages of the study. Did they try to avoid overlap?

Looking at SupplData9, I am confused about the numbers. I see 83 ME/CFS and 29 HC, not 83 and 48. And I see data for 57 proteins, not 77.

But anyway, the validation stage seemed to mostly agree with the first stage findings:

I think there's been talk of GDF15 on the forum. No difference here:

MCTS1, gene involved in T-cell lymphoma, most increased overall.

39 is Qi, P., Huang, M., and Li, T. (2022). Screening the Potential Biomarkers of COVID-19-Related Thrombosis Through Bioinformatics Analysis. Front Genet 13, 889348. https://10.3389/fgene.2022.889348.

 

And here’s links to the genecards (edit: put in a spoiler tag to not clog up the discussion)

Spoiler: Genecard links

Downregulated
MMP17
DPYSL3
PPM1F
WWP1
LDHB
H2AZ1
ID2
CXADR
COMP
ATP5IF1
ALDOA
CELF2
TAGLN3
ANTXR2
IFI16
VIM
YY1
GAPDH
H2BC21
H2AC1
H2BC21 (second hit)
H2BC12
H2BU1
H1-2
H1-10

Upregulated
MCTS1
FABP3
FABP4
FAB4 (this one is invalid, I think a typo and it was a second hit for FABP4)
CRABP2
ERP29
CFD
LIPG
CMPK1
TMED9
C6
RARRES2
FZD8
PGRMC1
GRIA4
PCSKIN
LMAN2
IL26
CANT1
TRAPPC3
FAM20A
PSMB3
OCRL
CHST12

 

What I see here is

1. A lot of evidence for reduced activity lowering levels of proteins.
2. The study is yet another powerful indicator that there is no inflammation or damage going on.
3. Hidden in plain sight is one increased protein of interest (the top one): MCTS1. Gene card says: "Notably, it positively regulates interferon gamma immunity to mycobacteria by enhancing the translation of JAK2 (PubMed:37875108)."

 

So there could be an MCTS1 variation that rather than impairing functionality here enhances it? Another one of the various contributory factors?

 

It only just struck me in the last few days that finding raised levels of a protein (or RNA) in patients may be more of a sign of a genetic predisposition than a 'driving force' in a process. That came up with CD24. I could never see why an acquired disease should push up CD24 across a whole cell population. But of course if it is a disease process that is facilitated by a genetic tendency to express more CD24 it is not a problem.

Here we are looking at proteomics so a raised MCTS1 protein could again either be just that process has set up that uses MCTS1 or it could be that people who tend to express a lot of MCTS1 are at risk of flipping in to this process. Either way the MCTS1 protein is presumably part of the process (unless there is linkage disequilibrium which I doubt) but in the second case you will not find the increased protein just restricted to the cells involved in the process. Moreover, you do not need to invoke some further upstream event that drives more MCTS1 as part of the process. The more MCTS1 comes with your genes.

 

That’s what I was wondering, cause or effect. Useful to know it could be either. I guess the only way we’ll know for sure is from genetic studies?

 

I wonder if the lack of highly sedentary controls could be a problem here. I haven't read the paper but from a quote above:

I don't think that matching for BMI is necessarily enough. I have a normal BMI but have lost muscle and gained fat, due to my extreme inactivity. One of those fancy electrical checks for body composition would have helped (the ones with proper kit where you get electrodes stuck all over you).

 

Perhaps we should be cautious in relying on genetic explanations for a disease with only weak heritability.Almost everything that will come up in any GWAS will be common (so widespread in the population) and with a weak effect (though the effect is most likely to be on gene expression). Many people with the illness won’t have the risk genotype. Should we expect such a small effect to show in a study like this, particularly given the level of correction for multiple comparisons?

 

I think that is important and it may be relevant to the Beentjes proteomics findings on lipid metabolism and insulin resistance. It may be hard to factor all these things out completely though.

 

Maybe, but I am just making the point that if we see proteins coming up on proteomics or cell labelling studies we should not just assume that the disease is switching them on. It may be that the disease occurs in people who always switch that protein on more. The protein is still likely to be involved in the disease but we don't have look for a mysterious signal in the disease mechanism that is pushing it up. If a disease occurs just because of normal processes overstepping a threshold then there may be no other extra mysterious cause.

Common polymorphisms can have quite big effects on disease. B27 has a huge predisposing effect for Reiter's but the heritability of Reiter's is probably very low - much lower than ME/CFS. The intriguing thing is that we still have no idea why B27 does this, since it seems to function the same way as all other HLA-B alleles. But we know it has major effects on expression of a whole range of infectious disease - so it is n't to do with one magic peptide fitting somewhere.

 

Interesting thought. I included in our paper an Indian paper that showed more gamma interferon responsiveness in women with TB. (And we did actually have a paragraph in brackets that suggested that women being more sensitive to gamma interferon signalling might obviate the need to invoke antibody!)