The -1438A/G polymorphism in the 5-hydroxytryptamine type 2A receptor gene affects promoter activity

Backgroun& The-1438A/G single nucleotide polymorphism (SAP) lies just upstream of two alternative promoters for the 5-bydroxytryptamine type 2A (5-HT2A) receptorgene (HTR2A) and is in strong linkage disequilibrium with the 102TICSNP. Both SNPs are associated with numerous psychiatric disorders and related phenotypes. A possible functional affect of tbe-1438A/G SNP might underlie associations of both linked SNPs with these neuropsycbiatric disorders. A prior investigation into affects of this SNP on promoterfunction, lacking the more downstream promoter, found no significant difference with a reporter gene assay. Methods: To investigate Possible functional effects of -1438A/G on either promoter, two different reporter gene assays were used in three cell lines. Results: Promoter activity was consistently detected that, in the presence of the SV40 enhancer, was significantly greater in the presence of the A allele relative to the G allele but only in cell lines that express endogenous HTR2A, suggesting that transcriptional factor(s) and the presence of both promoters might be necessary to elicit this effect. Conclusions: These findings show that the -1438A/G SNP has the potential to modulate HTR2A promoter activity and might be the functional variant responsible for the associations of both SNPs with many neuropsycbiatric phenotypes.