Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015674 (chronic fatigue syndrome)
 2,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic fatigue syndrome (CFS) is a debilitating disorder of unknown etiology with no known lesions, diagnostic markers or therapeutic intervention. The pathophysiology of CFS remains elusive, although abnormalities in the central nervous system (CNS) have been implicated, particularly hyperactivity of the serotonergic (5-hydroxytryptamine; 5-HT) system and hypoactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Since alterations in 5-HT signaling can lead to physiologic and behavioral changes, a genetic evaluation of the 5-HT system was undertaken to identify serotonergic markers associated with CFS and potential mechanisms for CNS abnormality. A total of 77 polymorphisms in genes related to serotonin synthesis (TPH2), signaling (HTR1A, HTR1E, HTR2A, HTR2B, HTR2C, HTR3A, HTR3B, HTR4, HTR5A, HTR6, and HTR7), transport (SLC6A4), and catabolism (MAOA) were examined in 137 clinically evaluated subjects (40 CFS, 55 with insufficient fatigue, and 42 non-fatigued, NF, controls) derived from a population-based CFS surveillance study in Wichita, Kansas. Of the polymorphisms examined, three markers (-1438G/A, C102T, and rs1923884) all located in the 5-HT receptor subtype HTR2A were associated with CFS when compared to NF controls. Additionally, consistent associations were observed between HTR2A variants and quantitative measures of disability and fatigue in all subjects. The most compelling of these associations was with the A allele of -1438G/A (rs6311) which is suggested to have increased promoter activity in functional studies. Further, in silico analysis revealed that the -1438 A allele creates a consensus binding site for Th1/E47, a transcription factor implicated in the development of the nervous system. Electrophoretic mobility shift assay supports allele-specific binding of E47 to the A allele but not the G allele at this locus. These data indicate that sequence variation in HTR2A, potentially resulting in its enhanced activity, may be involved in the pathophysiology of CFS.
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PMID:Genetic evaluation of the serotonergic system in chronic fatigue syndrome. 1807 67

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.
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PMID:Functional genomics of serotonin receptor 2A (HTR2A): interaction of polymorphism, methylation, expression and disease association. 2094 51

The serotonin receptor 5-HT2A (encoded by HTR2A) is an important regulator of fetal brain development and adult cognitive function. Environmental signals that induce epigenetic changes of serotonin response genes, including HTR2A, have been implicated in adverse mental health outcomes. The objective of this perspective article is to address the medical implications of HTR2A epigenetic regulation, which has been associated with both infant neurobehavioral outcomes and adult mental health. Ongoing research has identified a region of the HTR2A promoter that has been associated with a number of medical outcomes in adults and infants, including bipolar disorder, schizophrenia, chronic fatigue syndrome, borderline personality disorder, suicidality, and neurobehavioral outcomes. Epigenetic regulation of HTR2A has been studied in several different types of tissues, including the placenta. The placenta is an important source of serotonin during fetal neurodevelopment, and placental epigenetic variation of HTR2A has been associated with infant neurobehavioral outcomes, which may represent the basis of adult mental health disorders. Further analysis is needed to identify intrinsic and extrinsic factors that modulate HTR2A methylation, and the mechanism by which this epigenetic variation influences fetal growth and leads to altered brain development, manifesting in psychiatric disorders.
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PMID:The developmental basis of epigenetic regulation of HTR2A and psychiatric outcomes. 2504 77