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Joint associations of polymorphism, methylation and expression of serotonin receptor 2A (HTR2A) with Chronic Fatigue Syndrome
Author(s) -
Falkenberg Virginia Rebecca,
Unger Elizabeth R,
Rajeevan Mangalathu S
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.lb202
Subject(s) - epigenetics , dna methylation , cpg site , methylation , biology , allele , glucocorticoid receptor , genetics , promoter , genotype , epigenetics of physical exercise , transcription factor , gene , gene expression
Understanding the impact of genetic and epigenetic variations on gene expression is essential for understanding the genetic basis of complex diseases. The rs6311 (‐1438G/A) promoter polymorphism in the serotonin receptor 2A (HTR2A) gene is associated with Chronic Fatigue Syndrome (CFS). This polymorphism creates a binding site for the transcription factor E47 and disrupts a CpG methylation site resulting in a heritable difference in methylation. We analyzed methylation levels in HTR2A with DNA from peripheral blood mononuclear cells (PBMC) using pyrosequencing. A total of 17 CpG sites were examined in 88 subjects derived from a population‐based study of CFS. Methylation of three CpG sites at ‐1439, ‐1420, and ‐1224 were correlated with genotype at ‐1438G/A and/or CFS. Position ‐1420 is in a glucocorticoid response element, providing a molecular link for the interaction of glucocorticoid and serotonergic signaling systems. Position ‐1224 harbors an Sp1 binding site. Increased HTR2A expression in CFS appeared to originate from the preferential expression of the A allele compared to non‐fatigued control subjects. We constructed a model of HTR2A expression in CFS based on genetic and epigenetic variation at critical transcription factor binding sites. This integrated functional genomics approach may be highly relevant to defining the molecular determinants of human phenotypes. This study was funded by the CDC.