Preprint Dissecting the genetic complexity of myalgic encephalomyelitis/chronic fatigue syndrome via deep learning-powered genome analysis, 2025, Zhang+

Who can we look to to unfold the story? What sort of researchers will follow up on this? Wondering if they're already in the ME/CFS field or whether we can invite them in.

 

The paper pulls up HLA-C. Fluge also pulled up HLA-C. I realised that I don't have any real idea what the significance of C rather than A or B is. Maybe they are just much the same and we have three of them for diversity. But B seems to crop up more in disease associations. All of them crop up in certain common haplotypes but specific risk seems more to go with Class II or B. except psoriasis.

Does anyone know if C does something special?

 

My hunch is that they will be showing interest fairly soon. This is neurobiology and there are more neurobiologists in the UK than you have had hot dinners - literally.

 

This slide was shared today at the ME/CFS conference in Berlin, on the basis that B cells need T cell (th) signals in order to mature. They thus checked if those signals are changed leading to potential autoimmune processes in pwME.

Dubbed "plasma proteome of b/t cell secreted molecules". Very early, preliminary data.

Does any of this track with what you see in the data you're combing through atm?

 

I've been looking back at earlier papers with any remotely plausible links to the top ~22 or so results; I don't think we've discussed some of these papers so thought the list might be of some use to others:

Spoiler: Leptin

* Beentjes

* Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology (Stringer et al., 2013) - longitudinal, n=10, 25 consecutive days of blood draws, self-reported fatigue severity was significantly correlated with leptin levels in six of the participants with CFS and one healthy control

* A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome (Hoel et al., 2021) - 83 patients, 35 controls - Compared with the HC group, the ME/CFS group had slightly elevated mean insulin and leptin serum levels, as well as lower high molecular weight (HMW) adiponectin (Figure 7, A–C). However, this was primarily driven by the ME-M2 subset, as no significant or trending effect was seen for the others.

* The Role of Leptin and Inflammatory Related Biomarkers in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (Assil & Younger, 2021) - prospective, n=29, all F patients with ME/CFS, symptoms severity was associated with hyperleptinemia, inflammation and within-individual-variability of these biomarkers. Leptin and hsCRP may be clinically useful in predicting symptom severity.

* There was also a case report involving treatment of a patient with AN & ?ME/CFS with the synthetic analogue of leptin, metreleptin, in Rapid improvements of anorexia nervosa and probable myalgic encephalomyelitis/chronic fatigue syndrome upon metreleptin treatment during two dosing episodes (Hebebrand et al., 2023)

Spoiler: ACE

Serum angiotensin-converting enzyme as a marker for the chronic fatigue-immune dysfunction syndrome: A comparison to serum angiotensin-converting enzyme in sarcoidosis (Lieberman & Bell, 1993) - Serum ACE levels were elevated in 80% of patients with CFIDS and 30% of endemic control subjects as compared with 9.4% of non-endemic California control subjects

Association of medically unexplained fatigue with ACE insertion/deletion polymorphism in gulf war veterans (Vladutiu & Natelson., 2004) - Veterans with the DD genotype were eight times more likely to develop CFS/ICF than were those with the II genotype

Abnormalities of angiotensin regulation in postural tachycardia syndrome (Mustafa et al., 2011)

Spoiler: HLA-C

Human Leukocyte Antigen alleles associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) (Lande et al., 2020)

Spoiler: HDACs

Increased HDAC in association with decreased plasma cortisol in older adults with chronic fatigue syndrome (Jason et al., 2011) - Individuals with CFS display increased expression of HDAC 2 and 3, concomitant with decreased plasma cortisol. Those with CFS demonstrate lower total antioxidant power concomitant with down-regulation of the encoding gene NR3C1. Signaling dysregulation may exist in CFS, with increased HDAC expression along with reduced NR3C1 and cortisol expression.

 

Doesn't it have a more specialised role in KIR-mediated NK regulation?

 

It’s come up a few times in the virology lab I’m rotating in, it’s particularly important for NK activation and increased expression has been associated with better HIV protection. I don’t think that much is known about mechanism on that front, though.

[Edit: for interpretation, I think it’s important to remember that the association in this paper is for a predicted loss of function mutation in HLA-C]

 

I haven't had a closer look at the paper yet, nor have I been able to keep up with the discussion. My understanding is that they had different cohorts from different parts of the world (supposedly mainly US and UK and non-Europeans were excluded, whatever that may mean). The controls for each cohort were supposedly chosen from the same region as the ME/CFS cohort to not skew genetics too much. My understanding is that they then threw all the cohorts together. Does that not mean that in the end cohort you have an overepresentation of UK genes in the ME/CFS group which you are essentially comparing to a US group since the sample sizes for the UK control cohort are almost negligible unless you somehow accounted for that in your distribution of cohorts as well? Can one see anywhere how the end result of cohorts actually looks like? Of course these authors know what their doing so I think it's fair to assume they accounted for some form of skewing this could introduce.

 

At the risk of appearing foolish, I meant antigen, although I’m not sure if that is the right term. What I’m wondering is whether if is possible (even if it is improbable) that foreign molecules from a microbe or an environmental toxin could be acting directly or indirectly on the synapses to cause ME/CFS symptoms.

 

Wikipedia says it's very old. And doesn't give many disease associations, which is interesting.

Maybe it doesn't have many associations. But maybe it does have some, and no one's spotted them yet because they haven't got enough to go on.

 

This review might be useful:

HLA-C: An Accomplice in Rheumatic Diseases (2019, ACR Open Rheumatology)

 

Mmm... When I was going to meetings most of the stuff on KIR related to B and B27 protects against HIV too.

It would be ironic if we circle back to NK cells. I have reasons I cannot disclose to think that may not be the answer but it is all fascinating stuff.

 

I imagine it in a stripey jumper, wearing a mask and running away on its toes with a bag of swag over its shoulder.

 

I don't see the data pointing us that way, but anything is possible.

 

Judging by the abstract I am not enticed. They don't seem even to distinguish autoimmunity from auto inflammatory disease. I think the review might sum up as
" the exact mechanisms by which the HLA-C locus contributes to autoimmunity are largely undefined."

But I wonder whether there is some interplay between HLA-A, B and C that nobody has quite worked out yet. Maybe C alleles have implications for the way other MHC proteins operate. There are some very odd things about the system. We all inherit Class I alleles and KIR that should bind them, through different genes, but there seems to be no guarantee that the two will fit nicely together in any particular person.

 

I am thinking more of Sancho Panza or Baldrick.

 

I am excited for the diagnostic import of these findings. They would validate us. Just as happened with some channelopathies when genetic links were established (treatment still lags here, but the patient empowerment has been paradigm-changing).

I, too, however, wonder about the implications to treatment if antigen persistence is at play. If persistence plays a role, mightn't emergent treatment effects be transitory?

Regardless, as far as I am concerned, it's all about generating a legitimate diagnostic, and casting the BPS crowd and the insurance minions and all those shitty naysayers to the curb.

 

Well organophosphates affect the nerves. e.g. Countess of Mar who represented ME/CFS in the House of Lords for many years. See Wikipedia for details (link)

 

Well the replication set was only composed of the Cornell cohort. But maybe it's something to consider with regard to some of the specific genes picked out using the two cohorts that made up the discovery set.

 

HLA-B and C are usually in strong linkage disequilibrium as well