The CDC’s Pharmacogenomic’s Studies IV: Heredity and Chronic Fatigue Syndrome (ME/CFS)

How much a role heredity plays in who gets CFS has puzzled researchers since its onset. Several familial studies have found evidence that CFS tends to run in families. The methods some of these studies employed has, however, been criticized. A familial tendency towards CFS is also not synonymous with a genetic tendency towards it. This is because families share not only genes but a similar environment as well. Since it only takes one person to serve as a vector for a pathogen it is possible, for instance, for members of a family to face increased exposures to particular pathogen relative to the community around it. Twin studies can also help disentangle the effects of heredity and environment. Five twin studies have indicated from low (25%) to moderate (43-51%) effects of heredity. The largest twin study, done in 2005 found that heredity played a modest role in CFS. Just as in the other studies, however, there are methodological limitations to twin studies.

Another way to look at the heredity question is to assess whether there are increased rates of mutation in specific genes thought to play a role in CFS; thus far five studies have examined single nucleotide polymorphism (aka gene mutations) in an array of endocrine, neurological and immune genes. These are the focus of this edition of Phoenix Rising.

 

Single Nucleotide Polymorphism’s

SNP’s occur when a small spelling mistake occurs in one of the four nucleotide bases (ATCG) that make up our DNA. These mistakes are not uncommon – they occur – approximately 1 every 200 or so bases. In 1999, a consortium of pharmaceutical firms began a project to map 300,000 of the more common SNP’s. When they finished several years later, they had mapped about 3 million of them but estimate as many as 30 million exist. For a variation to be considered a SNP it must occur in over one percent of the population.

These alterations are important because they can subtly or sometimes dramatically alter the structure or function of the protein that the gene is coding for. Variations in SNP’s have been shown to impact how people respond to such varied factors as diseases, pathogens, toxins and pharmaceutical

drugs. While some diseases are caused by single mutations, researchers believe it probably takes many mutations to increase ones risk for such complex diseases such as cancer, diabetes, vascular diseases (and CFS).

The gene polymorphism studies, then, examine how important heredity – the genetic makeup one is born with – may be in CFS. The gene expression studies, on the other hand, measure what which genes are active at a single point in time. Although the two are different measures they are not unrelated; researchers are finding that people with different genetic make ups can have different gene expression results as well.

Inherited Neuroendocrine Gene Variations Contribute to CFS?

Goertzel, B., Pennachin, C., Coelho, L., Gurbaxani, B., Maloney, E. and J. Jones. 2006. Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome. Pharmacogenomics 7, 475-83.

Of all the Pharmacogenomics papers this one made the biggest splash in the press. It was this study that suggested CFS patients have a genetic predisposition to their disease centered in a group of mutations (single nucleotide polymorphisms (SNP’s)) occurring in a set of neuroendocrine genes. Most studies attempting to determine if a mutation in a genes increases one’s risk for a disease contrast how frequently that mutation occurs in patients versus controls. This study, like most others in these reports, took a systems approach. Instead of looking at whether one or a handful of polymorphisms were more commonly found in CFS patients, these researchers looked at a suite of about 50 inter-related neuroendocrine genes containing about 500 polymorphisms.

A Systems Approach - One of the central assumptions underlying the Pharmacogenomics projects seems to be that there is no silver bullet or single aberration waiting to be uncovered in CFS. Instead CFS is caused by a variety of problems, some subtle, some not-so-subtle, that combine together to create the condition we know as CFS. This idea is not unique to CFS – some researchers believe that broad systemic alterations underlie the problems in other complex, chronic diseases such as diabetes, heart disease, etc.

Findings - These researchers were able to differentiate CFS patients from healthy controls using a combination of 28 SNP’s occurring in eight neuroendocrine genes. This finding appears to confirm the systemic nature of the neuroendocrine involvement in CFS; it took mutations in a large set of genes before they were able to detect significant differences between the neuroendocrine mutation rates in CFS patients and the healthy controls. Does this suggest that the neuroendocrine vulnerability to CFS is both broad and shallow (?)

The researchers singled out five genes of special-interest:

Neuronal tryptophan hydroxylase (TH2) gene – involved in tryptophan breakdown and serotonin production

5-hydroxytryptamine transporter (HTT) gene – involved in transporting serotonin metabolites out of the cell

  • Serotonin – A vasoconstrictor and neurotransmitter, liberated by blood platelets, that inhibits gastric secretions and stimulates smooth muscle; present in relatively high concentrations in two areas of the central nervous system (basal ganglia, hypothalamus) that are of special interest in CFS. Smooth muscles are found in the internal organs including the lungs and lining the blood vessels. The vast majority of serotonin is not found in the brain but in the plasma, gastrointestinal tract and immune tissues.
  • An endocrinologist, Dr. Cleare, has posited that that reduced serotonin receptor activity (possibly in response to high serotonin levels) could cause a wide variety of involving sleep, pain, motivation and sexual activity among others in CFS and other diseases. Reduced serotonin activity has been found in both depression and anxiety.
  • A recent study finding of decreased gastric emptying in CFS suggests that low serotonin levels could also contribute to the gastrointestinal problems found in CFS. Both Dr. Cheney and Dr. De Meirleir believe that gut problems can contribute significantly to CFS. Several studies also suggest that low serotonin may contribute to the pain in FMS. Serotonin also plays a role in the distribution of on body fat – an intriguing finding given the increased waist/hip ratio’s found in CFS.
  • The 2003 Narita study found increased rates of a mutation in the in a serotonin transporter gene that results in increased serotonin uptake. By reducing serotonin levels in the synapses of the nerves this mutation could also lead to reduced serotonin activity in CFS. A recent study also suggested that reduced serotonin activity contributes to the pain in FMS. It is conceivable that altered serotonin activity in different parts of the brain contributes to the fatigue and pain in CFS and FMS respectively.

The catechol – O – methlytransferase (COMT) gene involved in regulating norepinephrine and epinephrine levels. Increased mutations rates of the COMT gene occur in some mood disorders.

  • Norepinephrine (NE) – a sympathetic nervous system (SNS) agent (catecholamine) produced in response to low blood pressure and physical stress, NE regulates blood flows (constricts blood vessels) and is an immune system regulator. Reduced NE levels could result in increased inflammation via increased TNF-a, IFN-y, nitric oxide production etc. Increased NE, on the other hand, could lead to reduced blood flows and predominantly anti-inflammatory cytokine production.
  • Epinephrine (E) (adrenaline) – another SNS catecholamine, epinephrine causes increased heart rate and force of contraction, vasoconstriction or vasodilation, relaxation of the bronchiolar and intestinal smooth muscles, glycogenolysis, lipolysis, and other metabolic effects. Epinephrine also helps regulate (inhibit) the immune response.

The cortisol receptor gene (NR31) and two genes for corticotropin releasing hormone receptors (CRHR1, CRHR2)

  • Corticotropin releasing hormone (factor) – sits at the top of the HPA axis. It stimulates the pituitary to produce ACTH which in turn prompts the adrenal glands to produce cortisol. A main initiator of the stress response, low CRH production could result in low cortisol levels.
  • Cortisol – the main adrenal stress hormone increases blood glucose levels (energy), moderates immune activity and regulates HPA axis activity during stress.

There is evidence of altered serotonin activity in CFS, increased norepinephrine levels and sympathetic nervous activity in CFS, reduced cortisol levels, and reduced responsiveness of HPA axis (CRH). These findings, therefore, are consistent with much of what we know of neuroendocrine functioning in CFS.

It is perhaps notable that four of the five genes regulate immune functioning and three of the five affect blood flows. The authors were not interested in these features but briefly noted that these genes affect the way the body responds to internal signals through the process of interoception.

INTEROCEPTION

The interoceptive system relates to the information conveyed to the spinal cord and the brain by sensory nerve cells returning from the organs, cardiovascular system, the skin and muscles. The Aslakson group studying subsets in CFS proposed that one of the three subsets of CFS patients and one of the two subsets of idiopathic fatigue patients identified were characterized by altered interoception. The interactions that serotonin, norepinephrine, epinephrine, cortisol and CRH have with the interceptive system suggests to these researchers that it may come into play in CFS.

This study appears to provide powerful evidence that CFS patients have inherited gene mutations that impair their responses to stressors such as exercise, infection, etc. How important these mutations are, however, is unclear. This study got the most attention in the press but was it the most significant? It was not a slam dunk. The authors stated that the accuracies – 75% accuracy in differentiating CFS patients from controls – did ‘not look spectacular’ and noted that researchers really like to see a 90%+ classification success rate.Some outside researchers have questioned the validity of the results given the relatively low number of samples. Others questioned whether other sets of polymorphisms might have produced better results. The authors noted that their accuracy would have been improved not by winnowing out some of the CFS patients but by eliminating those healthy controls who now or earlier had suffered from a bout of long-term unexplained fatigue. Surprisingly this turned out to apply to about 15% of the healthy controls and suggests these factors do play a role in the production of fatigue.

Despite the low accuracy levels displayed, the authors appeared to be quite enthusiastic about their results, saying

What is encouraging is that this rather mysterious and elusive illness called CFS appears to be finally yielding to attempts at biomarker discovery.”

This study is being enlarged and replicated in a different group of CFS patients. We didn’t have to wait long for a validation of its results. Just a month or so after the Pharmacogenomics studies were published we got word that another large research effort involving the same data base had been completed. In June the CAMDA (Critical Assessment of Microarray Data Analysis) conference met to report their results.

The Neuroendocrine Gene Mutations – A Summary From the CAMDA Conference - A presentation of the findings from that conference will appear shortly but a summaryof them indicates that many of the same gene mutations were highlighted in both efforts. The five studies that successfully examined the gene mutation data highlighted the following genes (some studies did multiple analyses).

  • Glucocorticoid receptor (cortisol) NR3C1 – 8
  • Tryptophan hydroxylase (TH) – 5
  • Corticotropin Releasing Hornone Receptor 2 (CRHR2) – 4
  • Catcehol-O-Methyltransferse (COMT) – 4
  • Monoamine Oxidase B (MAOB) – 4
  • Propiomelanocortin (POMC) – 4
  • Corticotropin Releasing Hormone Receptor 1 (CRHR1) – 2
  • Corticotropin Releasing Hormone (CRH) – 2

Given the fairly large data set (50 genes) the congruence of the results is remarkable and suggests that alterations in genes involved in hormonal (cortisol, corticotorpin releasing hormone) and neurotransmitter functioning (serotonin, norepinephrine/epinephrine, dopamine) interact in ways that predispose one to CFS.

To Pharmacogenomics Introduction / Pharma I: Allostatic Stress Pharma II: Gene Expression /

Pharma IV: Subsets

 

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