Researchers propose deep trawl of DNA to help uncover the causes of ME/CFS (Simon McG blog)

This is exciting, and crucial, research. Given that we have both the ICC criteria and recent work on characterising PEM, I think it'll be possible to design a screening tool that will rule out at least some people with other conditions or who have fatigue but not PEM.

 

@wigglethemouse
"Here is an example to describe what @Simon M is saying. Some folks believe mutations in the gene MBL2 play a role in making folks susceptible to ME. ... There are many gene mutations that can affect the bodies ability to fight infection. "​

Thanks, that is the kind of thing I am talking about.

A good question. As you say, the problem is that the infection rate of those exposed is very high, with only a few resistant to it. In this case conventional genetics, comparing at risk people got infected and the minority Who did not it’s probably more relevant.

Apparently, GWAS have turned up additional relevant genetic differences, in addition to those from conventional genetic studies. But as I’m struggling with a migraine I’m afraid you will have to do your own googling on this…

(I would expect the genetic differences identified to include those affecting genes involved in recognising the HIV virus as well as those that are expressed in T-helper cells, which are the cells that HIV infects. In fact, T-helper cells were only discovered as result of studying HIV)

thanks, Sasha. I know people had so many concerns about MEGA very understandable reasons. I think the study could be hugely important.

And I love that everybody can take part in including the severely affected who are normally excluded from studies.

that's an interesting question and I don't know if it's possible to look at that.

However, the examples I've seen (in my limited experience of the literature) have been of variants having an independent affects, as in the IL-23 Pathway Mentioned in the Blog:

Other autoimmune disease
Researchers have compared GWAS results from different illnesses to see if they have something in common – and autoimmune diseases often do. Findings from these studies have led to the identification of a common pathway for several diseases, one that includes an immune-regulating molecule called IL-23. As a result of this insight, existing drugs that are used to inhibit the IL-23 pathway in other diseases have become a mainstay treatment for several autoimmune conditions, including psoriasis and ankylosing spondylitis.
​

thanks, Kitty

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Not read it yet but thought it looked like it might add to the conversation.

Paywall, https://www.nature.com/articles/s41576-019-0127-1
Sci hub, https://sci-hub.se/10.1038/s41576-019-0127-1

 

As U.K. ME/CFS Biobank will be involved, I am sure that some sort of abbreviated version of their Participant Questionnaires would supply sufficient information:
to ascertain whether PEM is experienced,
where & when pain is experienced, whether constant, regular, daily......,
request a list of other diagnoses the patient may have,
whatever particular info the researchers may find useful.
There could be a quick version (for severe) or more detailed questionnaire (for those able to complete).
Please shout @Simon M if you need any patient guinea pigs to ‘test’ a questionnaire!


I had already thought of:
local support groups
regional #MEAction group
twitter friends
FB groups
Charity websites.......sure we could pull together to get the samples.

 

And I will be second in the Virtual Queue @Sasha

Fundraising possibilities @Simon M :

1) Any return envelope (pre paid from U.K.) for the pot could include a message:

“Please add a (xx)p stamp from the U.K. and help our research funds stretch a little further”

2) Consider asking for a voluntary donation for “the kit” (i.e. the survey/pot/SAE)?

Not at the application point, but include a donation slip (to include gift aid opportunity),
Or the link to a Fundraising Page, in with “the kit”

saying “if you are able to donate £5 (or more) towards this research, that would go towards the tests and if you can spare more that that would help a fellow PwME, who perhaps is not in a position to donate cash, just their sample”

^^^^ I'm thinking along the lines of Jack Monroe's Tin Can book - buy your own copy and pay for another copy which can be donated to the food bank for someone else who can't afford it.

 

Sorry, I've been away on vacation and so have not been following these discussions. Simon FWIW I think you've done an excellent job of explaining the strengths and limitations of a GWAS. On this issue of GWAS versus WGS (whole genome sequencing): GWAS asks 'what DNA letters that are *common* in the population predict ME status?' WGS asks 'what DNA letters that are *rare* (or even unique to the individual) predict ME status?' The difference comes from the GWAS technology sampling only a million or two letters for any person, whereas WGS reads out all 3 billion (or tries to). This GWAS technology is considerably cheaper than the WGS one and so can be applied at scale (thousands of people) whereas WGS of pwME's DNA is being done on dozens of people. Because of the large scale of GWAS it becomes feasible to robustly (i.e. statistically) say that a particular DNA variant is more likely to be in pwME than in healthy controls. Typically, this cannot be done with the dozens of WGS from pwME. Hope this is OK.

Another question I think has been "Will these be real cases of ME/CFS?" Yes! We will be consulting widely over this issue (of course) before the study plan is finalised, but the current idea is to start with the CureME Biobank inclusion/exclusion criteria (https://cureme.lshtm.ac.uk/researchers/inclusionexclusion-criteria/). A GWAS where each of the ~20k participants is assessed clinically would not be possible (too expensive) so the criteria used would need to be validated by subsampling participants and clinically assessing them. We expect different genetic contributions to ME risk ("genetic heterogeneity") and so do not wish to define ME using the narrowest criteria ("phenotypic homogeneity"). The narrowest criteria would disallow any chance of reaching 20k participants. I want to say - strongly - that PEM will be a primary inclusion criterion and that patient/carer groups will be involved centrally in drawing up the final study design and inclusion/exclusion criteria. I was around on the periphery of MEGA and see how some things need to be done better for this project. (We also need a name for the project - any ideas?)

 

Thanks for taking the time to reply, Chris – and for all your work on this.

Can you shed any light on whether/how GWAS could help if it transpired that ME was caused by a pathogen, as I asked above? My limited understanding is that it would help if ME was triggered by a pathogen in genetically predisposed individuals but that it would have been unlikely to help with the discovery of HIV or the prion which causes vCJD. Is that correct?

I think many of us are fed up with annoying acronyms like MEGA, PACE, GETSET etc. I would chose something that sounds dry, serious and scientific like the ME GWAS study.

Off topic, but I’m also hoping that the CMRC might be persuaded to change its name to reflect its new direction and focus.

 

Hi Robert. Yes, absolutely correct. Because the trigger (the pathogen) is not "written into" the DNA of individuals, we would not "see it". But what we can do is to detect what DNA letters predispose pwME to not recovering from these triggers. Knowing what the molecular/cellular deficit in recovery is becomes the first step to reversing the deficit.

OK: I like the ME GWAS. Nice and simple. I'll see what others thing.

CMRC: For clarity, "ME GWAS" is not a CMRC project. It is a joint venture between scientists such as myself and from the CureME Biobank, charities and pwME. There is a problem with losing the "C" in "CMRC" though because it then reverts to the "MRC" who are a main grant giving body! I'm less interested in names, and more interested in what can (needs to) be done. But I appreciate that, to some, names can evoke strong reactions!

 

Will patients from outside the UK be able to participate? Have you considered working with researchers in other countries to reach the 20k target faster? Or is that not viable.

 

I like it!

Should we start a thread for name suggestions for the project (so that this thread can focus on the science)?

 

Good point about acronyms.

But bear in mind that this project might need to recruit 20,000 people (more, since some won't meet the selection criteria). So we will be going well beyond the current ME online community, and reaching people who don't know much about research. I think ME GWAS won't mean anything to many pwME reading an article about the study in their local paper or hearing it on the radio. Maybe something with DNA or genetic in the title, something that most will recognise.

Along with ME, maybe: many people, esp outside the UK, won't recognise "ME" as they will have been told they have CFS. Even most US researchers (sadly) use CFS not ME or mecfs.

But name ideas are not my forte.

 

I've set up a thread for suggesting names:

https://www.s4me.info/threads/suggest-a-name-for-chris-pontings-me-gwas-project.10352/

 

Yes, my main concern is meeting this target. One thing that I need to find out is what are the restrictions from recruiting from outside the UK. This will be defined by the ethics committee governing the study so we won't know for a while.

 

What does the T stand for?

 

thymine

 

I keep reading GWAS as Gulf War.. so it has been confusing for me.

I would love to be able to participate in this study. I am in New Zealand though. It would be great if we could have a cohort that are a mix of patients from all around the world as one cohort group. I've never been in a ME study and would love to have the opportunity if it is possible.

 

Make that two of us

Also, if done well, the recruitment process could double as a sort of PR exercise for ME as a serious condition. Along the lines of "Wow! Somebody is prepared to look at the dna of 20,000 people - that must be something nasty they're looking for."

For example, the various charities may be able to get a few articles into the general press for the occasion. And, if it's legal, GPs could be asked to think of any ME patients they might have - yes, doctor, those heartsink ones you prefer not to think about - and be asked to give them an information sheet on the study.

 

What facilities/equipment/expertise would be needed to analyse the samples? If the project could be made 'modular' in some way, so that it's exact process could be replicated almost anywhere, could samples then not be analysed in different countries and the data pooled?

 

It seems there has just been a massive GWAS study published by King’s College London on anorexia. It had large UK cohort and large worldwide cohort. Some of the funding looks to have been the NIHR.
https://www.nature.com/articles/s41588-019-0439-2
Anorexia: Origins are complex mix of mind and body https://www.bbc.co.uk/news/health-48989359