Genetic Changes and ME/CFS: Identifying the CulpritJuly 21, 2016
Contrary to what some might think, our fate is not set upon conception when the genome is created, nor is our fate determined entirely upon the environment into which we are born and live. Instead, everything we are and everything we will be stems from a complex interaction between our genes and our environment, with the environment influencing which genes turn on and off and when, and our genes influence how we react to the environment.
For decades, scientists believed that while the genome was very plastic and could adapt to the environment in very early life, that window closed as we developed in utero. They also believed that genetic changes could only occur through changes to the underlying DNA. Today, however, an exciting new field called epigenetics has set that thinking on its head and created new possibilities for understanding how diseases develop — and how to prevent and treatment them.
Epigenetics refers to patterns of change in gene expression — not the gene itself — that occur in response to such things as nutrition, infection and physical and mental trauma, not genetic factors. These outside influences trigger a process called methylation that affects gene function but doesn’t change the underlying DNA structure.
“Epigenetics is really a funnel by which the outside environment interacts with the genome,” explains CFIDS Association grantee Patrick O. McGowan, Ph.D., assistant professor in the department of biological sciences at the University of Toronto in Canada. This, in turn, influences how cells work (or don’t work). Already, research shows that epigenetic changes are implicated in numerous diseases, including cancer, asthma and heart disease.
And, if Dr. McGowan is right, they may also play a role in the development of ME/CFS.
Disrupted Signaling in Body’s “Conductor”
To understand where Dr. McGowan and his team hope to go with their research, you first need to understand the hypothalamic-pituitaryadrenal (HPA) axis, often referred to as the “conductor” of our body and its responses.
The HPA is one of the most important communication pathways in the brain. The signals it produces (from hypothalamus to pituitary gland to the adrenal glands and back again) help maintain balance in the neuroendocrine system, which enables communication between various hormones throughout your body and your brain; and the sympathetic nervous system, which regulates the infamous “fight-or-flight” system and determines how the immune system responds to environmental stressors.
This latter component involves cortisol, a glucocorticoid hormone that helps dampen immune system inflammation and keep the body in balance. It also “turns on,” or activates, glucocorticoid receptors that then act on hundreds of genes that control development, metabolism, cognition and inflammation. Think of these receptors as a lock, and cortisol as the “key” that unlocks them to allow the hormone to enter the cell and tell it what to do. Yet one of the most consistent findings in ME/CFS is that patients don’t produce enough cortisol. Without that cortisol, immune system cells called lymphocytes continue to release pro-inflammatory cytokines, keeping the system activated and wreaking all sorts of havoc throughout the body. The whole process likely contributes to many of the symptoms of ME/CFS.
If Dr. McGowan is correct, epigenetic changes may be at the heart of this cortisol/cytokine imbalance.
Dr. McGowan’s research has three main goals:
- Confirm that there is, indeed, altered sensitivity to glucocorticoids and increased inflammatory cytokine production in immune system cells of people with ME/CFS.
- Identify patterns of DNA methylation and the specific epigenetic locations in the genome in people with ME/CFS.
- Analyze the epigenomic and genetic changes in ME/CFS patients in conjunction with symptoms, their severity and medication response — all areas associated with the HPA axis.
To do this, Dr. McGowan and his team will use immune system cells from the SolveCFS BioBank. They will first stimulate the cells with a synthetic glucocorticoid hormone to assess their sensitivity to glucocorticoids and cytokine production. They will also extract DNA from the blood cells to evaluate epigenetic patterns and compare the results to those of cells from people without ME/CFS. They also want to see if cells from different ME/CFS patients respond differently, which would provide evidence of subtypes of ME/CFS, something many researchers suspect exist.
“The exciting thing is that we’re looking across the entire genome, so we’re not making assumptions about what system is influencing the HPA abnormalities,” he says.
In addition to identifying potential epigenetic changes, Dr. McGowan and his team will also try to understand the environmental triggers that likely set about those changes. To do this, they will use disease-specific family history and current health reports for the patients whose cells they are examining.
Unlike genetic differences, which are fixed from conception and remain relatively stable across the lifespan, epigenetic differences are stable but respond to environmental factors; thus, Dr. McGowan said, they may be amenable to therapeutic intervention. For instance, some cancer drugs alter gene expression through epigenetic changes. But there are also potential lifestyle interventions that could have similar results, he said.
“I’m really excited about this grant because we are right at the beginning stages of being able to look at very complex diseases like ME/CFS in a holistic way” by targeting the genome, he said. “If we can start to get biomarkers for this disease that correlate with clusters of symptoms, we will have a better idea of how to approach interventions.” Those biomarkers could also make it easier to study ME/CFS, even aiding in early diagnosis of the disease and, possibly, approaches designed to prevent its development in susceptible individuals, as well as targets for treatment.
Learn more about epigenetics with this primer from The Scientist magazine: