From BMC Medical Genomics (open access), 23 February 2017.
Epigenetic modifications and glucocorticoid sensitivity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Wilfred C. de Vega(1,2), Santiago Herrera(1), Suzanne D. Vernon(3) and Patrick O. McGowan(1,2,4,5)
1. Department of Biological Sciences, University of Toronto
2. Department of Cell and Systems Biology, University of Toronto
3. Solve ME/CFS Initiative
4. Department of Psychology, University of Toronto.
5. Department of Physiology, Faculty of Medicine, University of Toronto
Abstract
BACKGROUND
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating idiopathic disease characterized by unexplained fatigue that fails to resolve with sufficient rest. Diagnosis is based on a list of symptoms and exclusion of other fatigue-related health conditions. Despite a heterogeneous patient population, immune and hypothalamic-pituitary-adrenal (HPA) axis function differences, such as enhanced negative feedback to glucocorticoids, are recurring findings in ME/CFS studies. Epigenetic modifications, such as CpG methylation, are known to regulate long-term phenotypic differences and previous work by our group found DNA methylome differences in ME/CFS, however the relationship between DNA methylome modifications, clinical and functional characteristics associated with ME/CFS has not been examined.
METHODS
We examined the DNA methylome in peripheral blood mononuclear cells (PBMCs) of a larger cohort of female ME/CFS patients using the Illumina HumanMethylation450 BeadChip Array. In parallel to the DNA methylome analysis, we investigated in vitro glucocorticoid sensitivity differences by stimulating PBMCs with phytohaemagglutinin and suppressed growth with dexamethasone. We explored DNA methylation differences using bisulfite pyrosequencing and statistical permutation. Linear regression was implemented to discover epigenomic regions associated with self-reported quality of life and network analysis of gene ontology terms to biologically contextualize results.
RESULTS
We detected 12,608 differentially methylated sites between ME/CFS patients and healthy controls predominantly localized to cellular metabolism genes, some of which were also related to self-reported quality of life health scores. Among ME/CFS patients, glucocorticoid sensitivity was associated with differential methylation at 13 loci.
CONCLUSIONS
Our results indicate DNA methylation modifications in cellular metabolism in ME/CFS despite a heterogeneous patient population, implicating these processes in immune and HPA axis dysfunction in ME/CFS. Modifications to epigenetic loci associated with differences in glucocorticoid sensitivity may be important as biomarkers for future clinical testing. Overall, these findings align with recent ME/CFS work that point towards impairment in cellular energy production in this patient population.
From the Journal of Investigative Medicine, 6 April 2017.
CNS findings in chronic fatigue syndrome and a neuropathological case report
Kimberly Ferrero(1), Mitchell Silver(1), Alan Cocchetto(2), Eliezer Masliah(3), Dianne Langford(1)
1. Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
2. State University of New York at Alfred, Engineering Technologies, Alfred, New York, USA
3. University of California San Diego, La Jolla, California, USA
Abstract
Chronic fatigue syndrome (CFS) is characterized as a persistent, debilitating complex disorder of unknown etiology, whereby patients suffer from extreme fatigue, which often presents with symptoms that include chronic pain, depression, weakness, mood disturbances, and neuropsychological impairment. In this mini review and case report, we address central nervous system (CNS) involvement of CFS and present neuropathological autopsy findings from a patient who died with a prior diagnosis of CFS.
Among the most remarkable pathological features of the case are focal areas of white matter loss, neurite beading, and neuritic pathology of axons in the white matter with axonal spheroids. Atypical neurons displaying aberrant sprouting processes in response to injury are observed throughout cortical gray and white matter. Abundant amyloid deposits identical to AD plaques with accompanying intracellular granular structures are observed as well. Neurofibrillary tangles are also present in the white matter of the frontal cortex, thalamus and basal ganglia.
Taken together, these neuropathological findings warrant further studies into CNS disease associated with CFS.
Yet again we are told, “..may be important as biomarkers…” and “.. these findings warrant further studies…”
I’ve lost count of how many times I’ve read statements like those.
More and more it seems to me that the principal beneficiaries of research are researchers. They build their scientific kudos by publishing ‘papers’ about every aspect of their work in order to attract more money for more research – but where is the result?
Money – research – publication – more money – more research – publication – etc.
Has anyone ever read a scientific report which ended “no more research needed”?
As a (non medical) researcher myself I may be biased, but no, more research is always needed. Don’t shoot the messenger, Solomon – what is needed desperately for ME is more funding for research so that these papers move from statements such as ‘may be important as biomarkers’ to statements such as ‘are shown to be effective treatments’.
I have a fear that the reason research into the cause of, and effective treatment of, ME/CFS/CFIDS seems to go round and round in circles (even if they seem to be decreasing circles until flung off at a tangent by fraudulent politically/specialty motivated ‘studies’) is because the cause is so fundamental and basic, and the treatment so simple, cheap and unpatentable. No-one seems to want to fund, or for that matter undertake, research these days unless there is a chance of a big pay out ($$$$) at the end of it.
If the answer to ME/CFS/CFIDS is as simple as; rest, vitamin/pseudovitamin and mineral nutritional supplementation, with a few ‘kick-starters’ such as; HMB, PQQ, chocolate and caffeine – no one individual or company is going to get rich or make greatly increased profits. Any research that may point to, or confirm, such an answer is only going to get funded by people like the ME Assoc’ and other non-profitable interested parties.
Oh, and by the way, if like me you are searching for the answer hidden in the haystack of science and other published papers regarding human metabolism, particularly of the mitochondria, you will not be surprised at the post mortem findings of Alzheimer Dementia (AD) like amyloid as many AD researchers are homing in on mitochondrial dysfunction as part of the early pathophysiology of AD. As well as researchers into; Parkinsons, Type II Diabetes, Cardiovascular Disease, Stroke, Breast and Prostate Cancer, Dyslexias, Autism, Depression, Schizophrenia …..