Epigenetic modifications and glucocorticoid sensitivity in Myalgic Encephalomyelitis

[ScottTriGuy]

Scott, did you possibly ask Wilfred about his opinion?

Just heard back from Will:

"This is a good question re: the differences in sensitivity and how it relates to Rituximab. The thing is, we are unable to conclude how these results relate to Rituximab as our study tested T cell sensitivity to dexamethasone. Rituximab, as you may already know, specifically targets B cells. Future research can address how dexamethasone sensitivity differs in B cells of ME patients."

 

[shannah]

The University of Toronto has recently interviewed Will de Vega and Patrick McGowan about their latest research paper on their epigenetic findings in Myalgic Encephalomyelitis.

“The patient response to this work has been eye-opening,” says de Vega, adding he’s received personal emails from patients who are looking for information."

“For years they have felt largely ignored and not taken seriously, so they’re happy to know there’s active research happening here in Canada.”

The hope, adds McGowan, is that by finding different epigenetic marks in CFS patients there’s an opportunity to develop treatments that can alter those marks.

“If you can identify specific epigenetic changes in the immune system of CFS patients, you can then start to develop ways of testing drugs already in use or develop new therapies."

The article is featured on the UTSC homepage.

http://ose.utsc.utoronto.ca/ose/story.php?id=9360

 

[boolybooly]

So I am wondering, are these the same two subgroups that Lipkin and Hornig discovered with their study on CFS CSF interleukins ?

 

[Helen]

So I am wondering, are these the same two subgroups that Lipkin and Hornig discovered with their study on CFS CSF interleukins ?

No. This subgroup is sensitive to glucocorticoids compared to normal/healthy people.

 

[boolybooly]

Did you see this bit though Helen?

Its buried a bit deep but they are saying there are two subgroups within the ME patient sample.

https://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-017-0248-3

Within the ME/CFS patient group, we observed two distinct subgroups based on in vitro sensitivity to glucocorticoid exposure.

We found 13 sites associated with glucocorticoid sensitivity in ME/CFS GC-Hypersensitive patients compared to both GC-typical ME/CFS patients and healthy controls.

So do the glucocorticoid hypersensitive / typical ME/CFS groups correspond with atypical / classical ME ? Its kind of rhetorical, I dont think we know but strikes me its a question worth asking and answering.

 

[Helen]

Did you see this bit though Helen?

They are saying there are two subgroups within the ME patient sample.

Yes, I did. ( I´m very interested in this as I have had severe adverse reactions to cortisone and I´m also allergic to wasp stings when cortisone is one of the acute drugs).

I just couldn´t see that the two subgroups had anything in common with the characteristics of the participants of the Lipkin/ Hornig group, but who knows, they might end up with similarities in future research .

 

[AdamS]

All I can say is...what a legend Will is, we need more young, curious, innovative researchers like this!

 

[Helen]

Cort Johnson has written an article on the study:

Epigenetics Study Highlights Metabolic Problems in Chronic Fatigue Syndrome (ME/CFS)
by Cort Johnson | Jul 30, 2017


https://www.healthrising.org/blog/2017/07/30/epigenetics-hpa-axis-chronic-fatigue/​

 

[FMMM1]

Follow ME in Denmark has an interesting article asking "Is GRAMD1A involved in the dysregulated sterol and sphingolipid homeostasis in ME patients?"


The article refers to the following papers:

1) "GRAM domain proteins specialize functionally distinct ER-PM contact sites in human cells" by Besprozvannaya et al [February 2018]; and

2) "Molecular basis for sterol transport by START-like lipid transfer domains". EMBO J. 2018 Feb 21. Horenkamp et al [February 2018]. GRAMD1A is a sterol transporter; and

3) "Epigenetic modifications and glucocorticoid sensitivity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)" by De Vega et al. The most hypermethylated gene associated with quality of life in ME patients was GRAMD1A.


Grateful if someone with more knowledge would comment. I.e. could De Vega's findings explain dysregulated sterol/sphingolipid/calcium homeostasis in ME patients?

 

[ScottTriGuy]

I emailed Will De Vega, his reply:

So for this particular finding on GRAMD1A, we disregarded case/control status and treated all subjects on a continuum to capture the mixed nature of the patient population. What the results suggest is that changes in the methylation of the GRAMD1A promoter region are linked to overall quality of life. Since there appears to be an average increase in methylation in ME compared to controls, this means that potential changes in GRAMD1A may have a role in disease severity. Classically, increased methylation in promoter regions lead to a decrease in expression of this gene, which may lead to differences in production of this protein and on its function. At most, we can say that there is a potential association between methylation and dysregulated cell signaling. However, we need additional studies to confirm this link between increased DNA methylation in GRAMD1A and its impact on downstream expression and function as we were unable to do this with our samples.

He also said:

In terms of ME research, our latest study which describes potential ME subtypes based on DNA methylation and health scores should be publicly available soon. We also submitted a different study that examines the genomic and epigenomic interactions in ME, which is currently under peer review.

 

[FMMM1]

I emailed Will De Vega, his reply:

So for this particular finding on GRAMD1A, we disregarded case/control status and treated all subjects on a continuum to capture the mixed nature of the patient population. What the results suggest is that changes in the methylation of the GRAMD1A promoter region are linked to overall quality of life. Since there appears to be an average increase in methylation in ME compared to controls, this means that potential changes in GRAMD1A may have a role in disease severity. Classically, increased methylation in promoter regions lead to a decrease in expression of this gene, which may lead to differences in production of this protein and on its function. At most, we can say that there is a potential association between methylation and dysregulated cell signaling. However, we need additional studies to confirm this link between increased DNA methylation in GRAMD1A and its impact on downstream expression and function as we were unable to do this with our samples.

He also said:

In terms of ME research, our latest study which describes potential ME subtypes based on DNA methylation and health scores should be publicly available soon. We also submitted a different study that examines the genomic and epigenomic interactions in ME, which is currently under peer review.

Thank you very much. Got the cold so I'm tired; can't take all of his in at the moment.