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 Pharmacogenomic's 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 (SNPs)) occurring in a set of neuroendocrine genes. Most studies attempting to determine if a mutation in a genes increases ones 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 production5-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 (See Central Fatigue 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 (click here). 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 ratios 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.
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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. An upcoming paper will examine what the interoceptive system is and how it might play a role in CFS.
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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 didnt 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.
Summary
- This is all encouraging stuff. Finding increased levels of gene mutations in CFS patients points researchers in the direction of the disease in this case they suggest CFS is a disease with impaired stress and immune responses. The confluence of neurodendocrine and immune gene mutations is particularly intriguing. In this case it suggests that CFS could both have a predisposition to produce more TNF-a than normal and a reduced ability to turn it off; i.e. CFS patients could, under the right circumstances, could have a tendency to chronic immune activation. Obviously there is more involved here that just inheritance many CFS patients are, after all, completely healthy until they get felled by whatever causes CFS but these studies have hopefully begun to unravel the unique vulnerabilities present in CFS and are pointing in the direction of whatever it is that brings things, often quite suddenly, to such a dramatic halt for so many CFS patients.