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Genetic evaluation of the serotonergic system in chronic fatigue syndrome.

Smith AK, Dimulescu I, Falkenberg VR, Narasimhan S, Heim C, Vernon SD, Rajeevan MS
Psychoneuroendocrinology 33:188-197, 2008 doi:10.1016/j.psyneuen.2007.11.001.

Summary

This paper extends our knowledge concerning involvement of the central nervous system, in particular dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and serotonergic systems, which are involved in modulation of the stress response. This paper used data generated during the Clinical Study of CFS in Wichita to explore polymorphisms (variations in DNA) related to serotonin synthesis, receptor signaling, transport, and catabolism (to view this study: http://www.cdc.gov/cfs/publications/casedef_10.htm). The Wichita Clinical Study enrolled 227 volunteers, from among the 7,162 fatigued and non-fatigued persons who had been followed between 1997 and 2000 (to view this study: http://www.cdc.gov/cfs/publications/surveillance_5.htm). Forty-three had CFS, 61 had unexplained fatigue not CFS (we call them ISF) and 60 were well controls (63 had a medical or psychiatric exclusionary condition identified and were ineligible). We extracted DNA from white blood cells, and examined polymorphisms by means of several methods. We found polymorphisms in different alleles of the HTR2A gene to be significantly more common in persons with CFS than in well controls (A allele 49% of CFS vs. 27% controls; T allele 47% of CFS 28% of controls; C allele 79% CFS 59% controls) and there were no differences in these alleles between persons with ISF and controls. This study provides the first genetic evaluation of the serotonergic system in CFS and the findings are in accord with other studies that have reported associations of the A and T alleles with several neuropsychiatric conditions.

Abstract

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.

Page last modified on October 27, 2008

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