Low gene expression conferred by association of an allele of the 5-HT2C receptor gene with antipsychotic-induced weight gain.
OBJECTIVE
Association has been reported between the C allele of a -759C/T polymorphism in the promoter of the 5-HT2C receptor gene (HTR2C) and antipsychotic-induced weight gain, suggesting that polymorphic HTR2C expression influences this phenotype. The authors tested this polymorphism, and other promoter variants, for effects on HTR2C transcription.


METHODS
Six HTR2C promoter haplotypes constructed from four polymorphisms were cloned into a luciferase reporter gene plasmid. Their transcriptional activities were then compared in two human cell lines.


RESULTS
All haplotypes containing the -759C allele showed less transcriptional activity than haplotypes containing the -759T allele. The A allele of a -997G/A polymorphism was also associated with reduced expression.


CONCLUSIONS
These findings suggest that the -759C allele is functional and results in relative underexpression of HTR2C. Reduced expression of HTR2C mRNA may underlie vulnerability to weight gain following antipsychotic treatment.
Buckland
Paul R
PR
Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK. buckland@cf.ac.uk
Hoogendoorn
Bastiaan
B
Guy
Carol A
CA
Smith
S Kaye
SK
Coleman
Sharon L
SL
O'Donovan
Michael C
MC
D000483:Alleles; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015992:Body Mass Index; D002460:Cell Line; D003024:Clozapine / Q000009:adverse effects* / Q000627:therapeutic use; D015870:Gene Expression / Q000235:genetics; D005819:Genetic Markers; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D009765:Obesity / Q000139:chemically induced* / Q000235:genetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics*; D012559:Schizophrenia / Q000188:drug therapy*; D014158:Transcription, Genetic / Q000235:genetics; D014162:Transfection / Q000379:methods; D015430:Weight Gain / Q000187:drug effects / Q000235:genetics
D014150:Antipsychotic Agents; D005819:Genetic Markers; D044405:Receptor, Serotonin, 5-HT2C; D003024:Clozapine