5-HT2C receptor gene polymorphisms associated with antipsychotic drug action alter promoter activity.
Polymorphisms within the 5-HT(2C) receptor gene promoter have been associated with several physiological and psychiatric phenotypes. Notably, the -759T allele has been associated with resistance to antipsychotic induced weight gain. This study assessed the activity of four promoter haplotypes expressed as luciferase constructs in the SH-SY5Y human neuroblastoma cell line in the presence or absence of a constitutively active 5-HT(2C) receptor. The presence of either -759T or -697C alleles reduced promoter activity. In addition a haplotype associated with resistance to antipsychotic induced weight showed under activity compared to the most common haplotype. In the presence of the 5-HT(2C) receptor a similar pattern of promoter activity was observed. Both -759C/T and -697G/C polymorphic sites are likely to play a role in basal promoter activity. Resistance to weight gain may, in part, be mediated by the consequences of reduced 5-HT(2C) receptor expression.
Hill
Matthew J
MJ
Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St. James' Hospital, James Street, Dublin, D8, Ireland. hillma@tcd.ie
Reynolds
Gavin P
GP
D014150:Antipsychotic Agents / Q000009:adverse effects*; D006801:Humans; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics*; D014162:Transfection; D015430:Weight Gain / Q000187:drug effects*
D014150:Antipsychotic Agents; D044405:Receptor, Serotonin, 5-HT2C