Should ME/CFS genetic research focus on using post-COVID ME/CFS and recovered COVID controls?

[forestglip]

Would that affect how the corrections for multiple testing is done, and potentially obfuscate leads?

Good question, I'm not sure how correction would work in that case.

 

[Jonathan Edwards]

I think you run into logistic problems if you want to characterise your groups precisely, too. It was touch and go getting enough ME/CFS versus controls. As soon. as you have conditions to meet recruitment or matched groups tends to plummet.

 

[forestglip]

I think it might be useful if it is possible to create a big cohort that meets those criteria, but ultimately it would only address one or two small facets of "susceptibility."

Very good points. It might be more trouble than it's worth if it only controls for a tiny portion of the phenomenon.

 

[jnmaciuch]

Very good points. It might be more trouble than it's worth if it only controls for a tiny portion of the phenomenon.

Still a useful exercise to think about, though! I think it just speaks to the limitations of GWAS (or any big data screening approach, really) and the danger of making runaway conclusions about mechanism solely on the basis of those results.

 

[forestglip]

I think it just speaks to the limitations of GWAS (or any big data screening approach, really) and the danger of making runaway conclusions about mechanism solely on the basis of those results.

Yes, my main fear that prompted the post was the ambiguity of, for example, an HLA allele finding. It might just cause people to get sick more severely and more often, which doesn't really seem that interesting in terms of how to treat ME/CFS if the subsequent disease process has nothing to do with HLA. There are ways that HLA could be central to the disease process, as Jonathan pointed out, but I'm just thinking about how to unravel if that is the case or not.

 

[Jonathan Edwards]

One point that may be relevant is that HLA pobably has relatively little to do with severity of acute infection. It takes many days for the HLA-mediated adaptive response to evolve. Nasty infections probably kill you before that. There are reasons to think that the adaptive immune response is more about not getting an illness twice than surviving one (and about providing a priming system for newborn adaptive immune systems).

There may be exceptions to this though. EBV would be a good candidate because a severe acute case is often one that progressively worsens over three weeks or so.

 

[jnmaciuch]

Yes, my main fear that prompted the post was the ambiguity of, for example, an HLA allele finding. It might just cause people to get sick more severely and more often, which doesn't really seem that interesting in terms of how to treat ME/CFS if the subsequent disease process has nothing to do with HLA. There are ways that HLA could be central to the disease process, as Jonathan pointed out, but I'm just thinking about how to unravel if that is the case or not.

It’s a good concern to have, and I think ultimately it’ll come down to mechanistic studies to confirm or deny. The aftermath of DecodeME will probably be a series of studies hypothesizing “well these genes suggest XYZ process might be involved, do we see additional evidence of that pathway being relevant? And if so, does targeting that process lead to any symptom improvement?”

And that will probably lead to a frustrating series of “nope, that’s not it” findings over a period of time. But I’m hopeful it’ll converge to an answer soon enough. It’ll just be prudent to keep that ambiguity in mind when we get the DecodeME results, and keep up the same level of scrutiny for any studies that follow up on it.

 

[hotblack]

This discussion and talk of variety and severity of infection at onset brings me back to thinking about variety and severity of ME/CFS, how much noise there would be in milder cases vs more severe and if we have enough severe cases (a few thousand in DecodeME) to usefully get information in that group alone.