TY - JOUR
T1 - Genetic evaluation of the serotonergic system in chronic fatigue syndrome
AU - Smith, Alicia K.
AU - Dimulescu, Irina
AU - Falkenberg, Virginia R.
AU - Narasimhan, Supraja
AU - Heim, Christine
AU - Vernon, Suzanne D.
AU - Rajeevan, Mangalathu S.
N1 - Funding Information:
The study was completely funded by the Centers for Disease Control and Prevention, a Federal Agency of US Government. The findings and conclusions of this study are those of the authors and do not necessarily represent the view of the funding agency.
Funding Information:
Support for A.K. Smith, V.R. Falkenberg, and S. Narasimhan was provided by the research participation program at the Centers for Disease Control and Prevention (CDC), National Center for Infectious Diseases, Division of Viral and Rickettsial Diseases, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the CDC. The authors wish to acknowledge the support of Dr. Elizabeth Maloney with statistical analysis and the support and encouragement of Dr. William Reeves with CFS genetics research.
PY - 2008/2
Y1 - 2008/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=38349121654&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=38349121654&partnerID=8YFLogxK
U2 - 10.1016/j.psyneuen.2007.11.001
DO - 10.1016/j.psyneuen.2007.11.001
M3 - Article
C2 - 18079067
AN - SCOPUS:38349121654
SN - 0306-4530
VL - 33
SP - 188
EP - 197
JO - Psychoneuroendocrinology
JF - Psychoneuroendocrinology
IS - 2
ER -
