Functional genomics of serotonin receptor 2A (HTR2A): interaction of polymorphism, methylation, expression and disease association

Abstract:

Serotonergic neurotransmission plays a key role in the pathophysiology of neuropsychiatric illnesses. The functional significance of a promoter polymorphism, -1438G/A (rs6311), in one of the major genes of this system (serotonin receptor 2A, HTR2A) remains poorly understood in the context of epigenetic factors, transcription factors and endocrine influences. We used functional and structural equation modeling (SEM) approaches to assess the contributions of the polymorphism (rs6311), DNA methylation and clinical variables to HTR2A expression in chronic fatigue syndrome (CFS) subjects from a population-based study. HTR2A was up-regulated in CFS through allele-specific expression modulated by transcription factors at critical sites in its promoter: an E47 binding site at position -1,438, (created by the A-allele of rs6311 polymorphism), a glucocorticoid receptor (GR) binding site encompassing a CpG at position -1,420, and Sp1 binding at CpG methylation site -1,224. Methylation at -1,420 was strongly correlated with methylation at -1,439, a CpG site that is dependent upon the G-allele of rs6311 at position -1,438. SEM revealed a strong negative interaction between E47 and GR binding (in conjunction with cortisol level) on HTR2A expression. This study suggests that the promoter polymorphism (rs6311) can affect both transcription factor binding and promoter methylation, and this along with an individual’s stress response can impact the rate of HTR2A transcription in a genotype and methylation-dependent manner. This study can serve as an example for deciphering the molecular determinants of transcriptional regulation of major genes of medical importance by integrating functional genomics and SEM approaches. Confirmation in an independent study population is required.

 

Source: Falkenberg VR, Gurbaxani BM, Unger ER, Rajeevan MS. Functional genomics of serotonin receptor 2A (HTR2A): interaction of polymorphism, methylation, expression and disease association. Neuromolecular Med. 2011 Mar;13(1):66-76. doi: 10.1007/s12017-010-8138-2. Epub 2010 Oct 13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044825/ (Full article)

 

Gut inflammation in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a debilitating disease characterized by unexplained disabling fatigue and a combination of accompanying symptoms the pathology of which is incompletely understood.

Many CFS patients complain of gut dysfunction. In fact, patients with CFS are more likely to report a previous diagnosis of irritable bowel syndrome (IBS), a common functional disorder of the gut, and experience IBS-related symptoms. Recently, evidence for interactions between the intestinal microbiota, mucosal barrier function, and the immune system have been shown to play a role in the disorder’s pathogenesis.

Studies examining the microecology of the gastrointestinal (GI) tract have identified specific microorganisms whose presence appears related to disease; in CFS, a role for altered intestinal microbiota in the pathogenesis of the disease has recently been suggested. Mucosal barrier dysfunction promoting bacterial translocation has also been observed. Finally, an altered mucosal immune system has been associated with the disease.

In this article, we discuss the interplay between these factors in CFS and how they could play a significant role in GI dysfunction by modulating the activity of the enteric nervous system, the intrinsic innervation of the gut. If an altered intestinal microbiota, mucosal barrier dysfunction, and aberrant intestinal immunity contribute to the pathogenesis of CFS, therapeutic efforts to modify gut microbiota could be a means to modulate the development and/or progression of this disorder.

For example, the administration of probiotics could alter the gut microbiota, improve mucosal barrier function, decrease pro-inflammatory cytokines, and have the potential to positively influence mood in patients where both emotional symptoms and inflammatory immune signals are elevated. Probiotics also have the potential to improve gut motility, which is dysfunctional in many CFS patients.

 

Source: Lakhan SE, Kirchgessner A. Gut inflammation in chronic fatigue syndrome. Nutr Metab (Lond). 2010 Oct 12;7:79. doi: 10.1186/1743-7075-7-79. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964729/ (Full article)

 

Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity

Abstract:

BACKGROUND: The aim of this study was to investigate the possibility that a decreased mitochondrial ATP synthesis causes muscular and mental fatigue and plays a role in the pathophysiology of the chronic fatigue syndrome (CFS/ME).

METHODS: Female patients (n = 15) and controls (n = 15) performed a cardiopulmonary exercise test (CPET) by cycling at a continuously increased work rate till maximal exertion. The CPET was repeated 24 h later. Before the tests, blood was taken for the isolation of peripheral blood mononuclear cells (PBMC), which were processed in a special way to preserve their oxidative phosphorylation, which was tested later in the presence of ADP and phosphate in permeabilized cells with glutamate, malate and malonate plus or minus the complex I inhibitor rotenone, and succinate with rotenone plus or minus the complex II inhibitor malonate in order to measure the ATP production via Complex I and II, respectively. Plasma CK was determined as a surrogate measure of a decreased oxidative phosphorylation in muscle, since the previous finding that in a group of patients with external ophthalmoplegia the oxygen consumption by isolated muscle mitochondria correlated negatively with plasma creatine kinase, 24 h after exercise.

RESULTS: At both exercise tests the patients reached the anaerobic threshold and the maximal exercise at a much lower oxygen consumption than the controls and this worsened in the second test. This implies an increase of lactate, the product of anaerobic glycolysis, and a decrease of the mitochondrial ATP production in the patients. In the past this was also found in patients with defects in the mitochondrial oxidative phosphorylation. However the oxidative phosphorylation in PBMC was similar in CFS/ME patients and controls. The plasma creatine kinase levels before and 24 h after exercise were low in patients and controls, suggesting normality of the muscular mitochondrial oxidative phosphorylation.

CONCLUSION: The decrease in mitochondrial ATP synthesis in the CFS/ME patients is not caused by a defect in the enzyme complexes catalyzing oxidative phosphorylation, but in another factor.

TRIAL REGISTRATION: CLINICAL TRIALS REGISTRATION NUMBER: NL16031.040.07.

 

Source: Vermeulen RC, Kurk RM, Visser FC, Sluiter W, Scholte HR. Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity. J Transl Med. 2010 Oct 11;8:93. doi: 10.1186/1479-5876-8-93. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964609/ (Full article)

 

Current status of xenotropic murine leukemia virus-related retrovirus in chronic fatigue syndrome and prostate cancer: reach for a scorecard, not a prescription pad

Xenotropic murine leukemia virus-related retrovirus (XMRV) is a newly discovered member of the gammaretrovirus genus of retroviruses, which has been recently associated with 2 human disorders, prostate cancer and chronic fatigue syndrome [1]. Since it was first reported in 2006, XMRV has been intensely investigated, but no clear picture of prevalence, geographic distribution, or disease association has emerged. In this issue of the Journal, 3 studies shed new light on the presence of XMRV in human populations.

You can read the rest of this comment here: http://jid.oxfordjournals.org/content/202/10/1463.long

 

Comment on:

Detection of xenotropic murine leukemia virus-related virus in normal and tumor tissue of patients from the southern United States with prostate cancer is dependent on specific polymerase chain reaction conditions. [J Infect Dis. 2010]

Failure to detect xenotropic murine leukemia virus-related virus in blood of individuals at high risk of blood-borne viral infections. [J Infect Dis. 2010]

Xenotropic murine leukemia virus-related virus prevalence in patients with chronic fatigue syndrome or chronic immunomodulatory conditions. [J Infect Dis. 2010]

 

Source: Kearney M, Maldarelli F. Current status of xenotropic murine leukemia virus-related retrovirus in chronic fatigue syndrome and prostate cancer: reach for a scorecard, not a prescription pad. J Infect Dis. 2010 Nov 15;202(10):1463-6. doi: 10.1086/657169. Epub 2010 Oct 11. http://jid.oxfordjournals.org/content/202/10/1463.long (Full article)

 

Xenotropic murine leukemia virus-related virus prevalence in patients with chronic fatigue syndrome or chronic immunomodulatory conditions

Abstract:

We investigated the prevalence of xenotropic murine leukemia virus-related virus (XMRV) among 293 participants seen at academic hospitals in Boston, Massachusetts. Participants were recruited from the following 5 groups of patients: chronic fatigue syndrome (n = 32), human immunodeficiency virus infection (n = 43), rheumatoid arthritis (n = 97), hematopoietic stem-cell or solid organ transplant (n = 26), or a general cohort of patients presenting for medical care (n = 95). XMRV DNA was not detected in any participant samples. We found no association between XMRV and patients with chronic fatigue syndrome or chronic immunomodulatory conditions.

Comment in: Current status of xenotropic murine leukemia virus-related retrovirus in chronic fatigue syndrome and prostate cancer: reach for a scorecard, not a prescription pad. [J Infect Dis. 2010]

 

Source: Henrich TJ, Li JZ, Felsenstein D, Kotton CN, Plenge RM, Pereyra F, Marty FM, Lin NH, Grazioso P, Crochiere DM, Eggers D, Kuritzkes DR, Tsibris AM. Xenotropic murine leukemia virus-related virus prevalence in patients with chronic fatigue syndrome or chronic immunomodulatory conditions. J Infect Dis. 2010 Nov 15;202(10):1478-81. doi: 10.1086/657168. Epub 2010 Oct 11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2957553/ (Full article)

 

Exploring the feasibility of establishing a disease-specific post-mortem tissue bank in the UK: a case study in ME/CFS

Abstract:

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a condition, the aetiology of which remains controversial, and there is still no consensus on its nature and determination. It has rarely been studied in post-mortem examinations, despite increasing evidence of abnormalities from neuroimaging studies.

AIM: To ascertain the feasibility of developing a national post-mortem ME/CFS tissue bank in the UK, to enhance studies on aetiology and pathogenesis, including cell and tissue abnormalities associated with the condition.

METHODS: The case study was carried out combining qualitative methods, ie, key informant interviews, focus group discussions with people with ME/CFS, and a workshop with experts in ME/CFS or in tissue banking.

RESULTS AND CONCLUSIONS: The study results suggest that the establishment of the post-mortem ME/CFS tissue bank is both desirable and feasible, and would be acceptable to the possible tissue donors, provided that some issues were explicitly addressed.

 

Source: Lacerda EM, Nacul L, Pheby D, Shepherd C, Spencer P. Exploring the feasibility of establishing a disease-specific post-mortem tissue bank in the UK: a case study in ME/CFS. J Clin Pathol. 2010 Nov;63(11):1032-4. doi: 10.1136/jcp.2010.082032. Epub 2010 Oct 5. https://www.ncbi.nlm.nih.gov/pubmed/20924033

 

Blood pressure variability and closed-loop baroreflex assessment in adolescent chronic fatigue syndrome during supine rest and orthostatic stress

Abstract:

Hemodynamic abnormalities have been documented in the chronic fatigue syndrome (CFS), indicating functional disturbances of the autonomic nervous system responsible for cardiovascular regulation.

The aim of this study was to explore blood pressure variability and closed-loop baroreflex function at rest and during mild orthostatic stress in adolescents with CFS. We included a consecutive sample of 14 adolescents 12-18 years old with CFS diagnosed according to a thorough and standardized set of investigations and 56 healthy control subjects of equal sex and age distribution.

Heart rate and blood pressure were recorded continuously and non-invasively during supine rest and during lower body negative pressure (LBNP) of -20 mmHg to simulate mild orthostatic stress. Indices of blood pressure variability and baroreflex function (α-gain) were computed from monovariate and bivariate spectra in the low-frequency (LF) band (0.04-0.15 Hz) and the high-frequency (HF) band (0.15-0.50 Hz), using an autoregressive algorithm.

Variability of systolic blood pressure in the HF range was lower among CFS patients as compared to controls both at rest and during LBNP. During LBNP, compared to controls, α-gain HF decreased more, and α-gain LF and the ratio of α-gain LF/α-gain HF increased more in CFS patients, all suggesting greater shift from parasympathetic to sympathetic baroreflex control. CFS in adolescents is characterized by reduced systolic blood pressure variability and a sympathetic predominance of baroreflex heart rate control during orthostatic stress. These findings may have implications for the pathophysiology of CFS in adolescents.

 

Source: Wyller VB, Barbieri R, Saul JP. Blood pressure variability and closed-loop baroreflex assessment in adolescent chronic fatigue syndrome during supine rest and orthostatic stress. Eur J Appl Physiol. 2011 Mar;111(3):497-507. doi: 10.1007/s00421-010-1670-9. Epub 2010 Oct 2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037975/ (Full article)

 

Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: an experimental study

Abstract:

OBJECTIVE: The aims of this study were to examine: (i) baseline pressure pain thresholds in patients with chronic fatigue syndrome and those with chronic low back pain compared with healthy subjects; (ii) the change in mean pain threshold in response to exercise; and (iii) associations with exercise-induced increase in nitric oxide.

PARTICIPANTS: Twenty-six patients with chronic fatigue syndrome suffering of chronic pain, 21 patients with chronic low back pain and 31 healthy subjects.

METHODS: Participants underwent a submaximal aerobic exercise protocol on a bicycle ergometer, preceded and followed by venous blood sampling (nitric oxide) and algometry (hand, arm, calf, low back).

RESULTS: Patients with chronic fatigue syndrome presented overall lower pain thresholds compared with healthy subjects and patients with chronic low back pain (p < 0.05). No significant differences were found between healthy subjects and patients with chronic low back pain. After submaximal aerobic exercise, mean pain thresholds decreased in patients with chronic fatigue syndrome, and increased in the others (p < 0.01). At baseline, nitric oxide levels were significantly higher in the chronic low back pain group. After controlling for body mass index, no significant differences were seen between the groups at baseline or in response to exercise. Nitric oxide was not related to pain thresholds in either group.

CONCLUSION: The results suggest hyperalgesia and abnormal central pain processing during submaximal aerobic exercise in chronic fatigue syndrome, but not in chronic low back pain. Nitric oxide appeared to be unrelated to pain processing.

 

Source: Meeus M, Roussel NA, Truijen S, Nijs J. Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: an experimental study. J Rehabil Med. 2010 Oct;42(9):884-90. Doi: 10.2340/16501977-0595. https://www.medicaljournals.se/jrm/content/html/10.2340/16501977-0595 (Full article)

 

Effectiveness of stepped care for chronic fatigue syndrome: a randomized noninferiority trial

Abstract:

OBJECTIVE: In this randomized noninferiority study, the effectiveness and efficiency of stepped care for chronic fatigue syndrome (CFS) was compared to care as usual. Stepped care was formed by guided self-instruction, followed by cognitive behavior therapy (CBT) if the patient desired it. Care as usual encompassed CBT after a waiting period.

METHOD: A total of 171 CFS patients were randomly allocated to stepped care or care as usual. Patients in both conditions were assessed 3 times: at baseline, after guided self-instruction or the waiting period, and after CBT. The primary outcome variables were fatigue severity (Checklist Individual Strength) and disabilities (Sickness Impact Profile and Medical Outcomes Survey Short Form-36).

RESULTS: An intention to treat analysis showed that stepped care (N = 84) for CFS is noninferior to care as usual (N = 85). Both conditions were equivalent in reducing fatigue severity, reducing disabilities, and increasing physical functioning. The treatment results of both conditions were in accordance with those of previous randomized controlled trials testing the effectiveness of CBT for CFS. The total therapist time needed to treat a patient was significantly less in the stepped care condition.

CONCLUSIONS: Stepped care is as effective as CBT and is more time efficient for the therapist.

Copyright 2010 APA, all rights reserved.

 

Source: Tummers M, Knoop H, Bleijenberg G. Effectiveness of stepped care for chronic fatigue syndrome: a randomized noninferiority trial. J Consult Clin Psychol. 2010 Oct;78(5):724-31. doi: 10.1037/a0020052. https://www.ncbi.nlm.nih.gov/pubmed/20873907

 

A national cross-sectional survey of diagnosed sufferers of myalgic encephalomyelitis/chronic fatigue syndrome: pathways to diagnosis, changes in quality of life and service priorities

Abstract:

BACKGROUND: The diagnosis and treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is subject to debate.

AIMS: To measure the time to diagnosis and services accessed.

METHOD: A national cross-sectional study. A profile and service utilisation questionnaire, information on the pathways to diagnosis, the WHOQoL Brief and a listing of priorities of the needs of participants were used. Individuals were invited to participate if they had a medical diagnosis of ME/CFS.

RESULTS: A total of 211 surveys were returned. Prior to diagnosis sufferers accessed on average 4.5 services after their initial consultation. The mean time to diagnosis was 3.7 years but time ranged from 0 to 34 years. Quality of life deteriorated post-onset. The priority for future service provision was increased understanding and diagnosis of ME/CFS by the medical profession.

CONCLUSION: In order to alleviate the burden on the sufferer there is a greater need for education on this condition.

 

Source: Comiskey C, Larkan F. A national cross-sectional survey of diagnosed sufferers of myalgic encephalomyelitis/chronic fatigue syndrome: pathways to diagnosis, changes in quality of life and service priorities. Ir J Med Sci. 2010 Dec;179(4):501-5. doi: 10.1007/s11845-010-0585-0. Epub 2010 Sep 26. https://www.ncbi.nlm.nih.gov/pubmed/20872086