Polymorphisms in the regulatory region of the human serotonin 5-HT2A receptor gene (HTR2A) influence gene expression

Background: Genowic variation in the regulatory region of the serotonin (5-HT) 2A receptor gene (HTR2A) may contribute to altered levels of 5-HT2A receptor and to psychiatric disease. Methods: Frequency and linkage disequilibrium (LD) were determined for promoter single nucleotide polymorphisms (SNPs) -1438A/G, -1420C/T, and -783A/G in 150 subjects. Functional relevance -1438A/G and -783A/G was assayed in vitro using a luciferase reporter assay and ex vivo using quantitative real time polymerase chain reaction in a set of human fibroblast cell lines. Results: Significant LD was observed between SNPs -1438A/G and -783A/G. In vitro assays showed no significant differences in promoter activity between theA- and G-allele of -1438 locus when expressed with the major alleles at -1420OC/T and -783A/G. however when the minor allele G at -783 was expressed with G-allele at -1438, promoter activity was significantly decreased. 5-HT2A receptor mRNA expression in human fibroblast cell lines confirmed that -783A/G polymorphism significantly modified the effects of -1438A/G SNR Conclusions: Our results demonstrate that SNP-783AIG modyic s the effects of the major SNP -1438A/G. Future studies examining the association of-1438A/polymorphism with diseases and 5-HT2A receptor expression analyses should account for this epistasis,