Genome-epigenome interactions associated with ME/CFS, 2018, McGowan et al.

Abstract broken into short paragraphs for ease of reading.

ABSTRACT

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease of unknown etiology. Multiple studies point to disruptions in immune functioning in ME/CFS patients as well as specific genetic polymorphisms and alterations of the DNA methylome in lymphocytes. However, potential interactions between DNA methylation and genetic background in relation to ME/CFS have not been examined.

In this study we explored this association by characterizing the epigenetic (~480 thousand CpG loci) and genetic (~4.3 million SNPs) variation between cohorts of ME/CFS patients and healthy controls.

We found significant associations of DNA methylation states in T-lymphocytes at several CpG loci and regions with ME/CFS phenotype. These methylation anomalies are in close proximity to genes involved with immune function and cellular metabolism. Finally, we found significant correlations of genotypes with methylation modifications associated with ME/CFS.

The findings from this study highlight the role of epigenetic and genetic interactions in complex diseases, and suggest several genetic and epigenetic elements potentially involved in the mechanisms of disease in ME/CFS.
Click to expand...
 
For the ladies...

"...
The SNP that we found in signifi- cant association with ME/CFS in females, rs11712777
...
rs11712777, and the genes in LD with it, form an expression quantitative trail loci (eQTL) alter- ing the expression of the CCK (cholecystokinin peptide hormone) gene. CCK has a number of active forms, expressed in a variety of tissues, including the intestine and blood [32], and plays a role in appetite, body weight and immune sys- tem function [32,33]. A rat knockout (KO) of the cholecystokinin B receptor (CCKBR) shows atte- nuated sickness behaviour [34]. This sickness behaviour in rats has remarkable similarity to some of the symptoms of ME/CFS [35], including fatigue, malaise, hyperalgesia, sleepiness, anhedo- nia, weight loss and diminished activity [35]. CCK is also co-localized with sleep-promoting preoptic neurons in the hypothalamus [36], which may relate to fatigue and unrefreshing sleep symptoms in ME/CFS. Finally, recent evi- dence suggests that CCK has a role regulating the differentiation of CD4+ T-cells [37], and that CCK-expressing neurons are a critical cellular component of the hypothalamic–pituitary–adre- nal axis [38]. These roles of CCK in components of the immune system are consistent with sug- gested immune dysregulation in ME/CFS
 
Regarding SNPS:
Of the 2 million SNPS analysed, nothing was significant in the total sample population:
None of the more than 2 million variable SNP loci targeted in this study with the Human Omni 5–4 Array (Illumina Inc.) had a significant association (α = 0.05) with ME/CFS after p-value corrections ... when data from both sexes were analysed together (healthy control, n = 48 vs. ME/CFS, n = 61).
Click to expand...

When they just looked at females, they found one significant SNP:
we performed independent analyses of data from females only (healthy control, n = 27 vs. ME/CFS, n = 34). These analyses revealed a significant asso- ciation (χ2 genotypic test, permutation-corrected p-value = 0.0374, OR = 0.1845, 1/OR = 5.42) of one SNP (rs11712777, chr3:42347678) with the ME/CFS disease phenotype.
Click to expand...

And even that finding wasn't very strong:
While CCK-associated variant rs11712777 may be a biologically relevant candidate influencing susceptibility to ME/CFS, our findings suggest that it only accounts for a small fraction of the risk (OR = 0.1845).
Click to expand...
And there was no result consistent with other genetic association studies (although no other studies had looked at rs11712777):
There were no other overlaps in the SNPs or genes associated with ME/CFS between this study and previous genetic association studies.
Click to expand...
 
It seems that there are now several different teams doing work on genetics and epigenetics in small groups of patients. I really hope they will put all the genome data together to do a bigger study. Surely that would be much more powerful than lots of little studies each finding small associations that might just be chance variation.
The Alan Light talk this week looked at a bigger sample and focused on genes related to immunological and energy processes and found some potentially interesting associations.
https://www.s4me.info/threads/lives...ations-create-susceptibility-for-me-cfs.7072/
 
So these were 61 ME/CFS patients from the Bateman Horne Center whose blood samples were shipped to the University of Toronto. There they looked at (1) immune markers (2) genetic and (3) epigenetic variation in comparison to 48 healthy controls. Unfortunately the analyses seem to have yielded mostly null results.

(1): "There were no differences between patients and controls in the relative proportions of CD19+ B-cells, CD14+ monocytes, CD3+ T-cells, CD4+/CD8- ‘helper’ T-cells or CD4-/CD8+ T-cells in PBMC lymphocyte samples."

(2): "None of the more than 2 million variable SNP loci targeted in this study with the Human Omni 5–4 Array (Illumina Inc.) had a significant association (α = 0.05) with ME/CFS after p-value corrections."

(3): "Of the 467,971 CpG loci targeted with the Human Methylation 450K Array (Illumina Inc.), 141 had significant associations with the ME/CFS phenotype (raw p-value < 0.05) [...] None of these differentially methylated loci were significant after FDR corrections. [...] These results are in contrast with previous findings by our group, which revealed thousands to tens of thousands of differentially methylated CpG loci associated with ME/CFS in PBMCs, using the same 450K array."
​
 
Blog from the Bateman Horne Centre on this study, http://batemanhornecenter.org/influence-genetics-epigenetics-cfs/
This research would not have been possible without the Bateman Horne Center. BHC recognizes the opportunity for discovery that ME/CFS and FM represents. We identify and partner with the best and the brightest scientists to accelerate research for the diagnosis and treatment of ME/CFS and FM by leveraging our research ready patient population. The samples and clinical data BHC provided to McGowan for his research represent $75,000 in value. This means that our science partners like McGowan don’t need to use their precious grant funds on recruitment and sample collection and can focus on innovation and discovery. Read more about BHC’s strategic plan to advances research and mainstream ME/CFS here.
Click to expand...
 
Michiel Tack said:
So these were 61 ME/CFS patients from the Bateman Horne Center whose blood samples were shipped to the University of Toronto. There they looked at (1) immune markers (2) genetic and (3) epigenetic variation in comparison to 48 healthy controls. Unfortunately the analyses seem to have yielded mostly null results.

(1): "There were no differences between patients and controls in the relative proportions of CD19+ B-cells, CD14+ monocytes, CD3+ T-cells, CD4+/CD8- ‘helper’ T-cells or CD4-/CD8+ T-cells in PBMC lymphocyte samples."

(2): "None of the more than 2 million variable SNP loci targeted in this study with the Human Omni 5–4 Array (Illumina Inc.) had a significant association (α = 0.05) with ME/CFS after p-value corrections."

(3): "Of the 467,971 CpG loci targeted with the Human Methylation 450K Array (Illumina Inc.), 141 had significant associations with the ME/CFS phenotype (raw p-value < 0.05) [...] None of these differentially methylated loci were significant after FDR corrections. [...] These results are in contrast with previous findings by our group, which revealed thousands to tens of thousands of differentially methylated CpG loci associated with ME/CFS in PBMCs, using the same 450K array."
​
Click to expand...
I have not read the paper, so this may be drivel. To me it is not one thing, one expression that we should be lookong for in a systems condition. It is combinations which may be expressed more significantky in ME/ CFS.

It is a systems condition and expression will be modulated by original inherited condition, epigentic expression and the effect this triggers on multiple other genes and thus processes?

Or am i just not getting it ?
 
You must log in or register to reply here.
Back
Top Bottom