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Title: The functional consequences of 5-HT2C receptor gene promoter polymorphisms associated with antipsychotic drug action
Author: Hill, M. J.
ISNI:       0000 0001 2445 3600
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2008
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The advent of atypical antipsychotics as a pharmacotherapy for schizophrenia was accompanied by a change in side-effects experienced by patients. While the prevalence ofmovement disorders was reduced it became apparent thatocertain atypical medicatior:s could produce substantial weight gain. Initial pharmacogenetic studies associated the liability for weight gain with single nucleotide polymorphislns in the 5' region ofthe 5-HT2C receptor gene. This receptor is located within the hypothalamus and has long been known to control aspects of feeding. It was shown that carriers of the - 759T allele were resistant to antipsychotic induced weight gain compared to carriers ofthe -759C allele. Promoter polymorphisms may influence the regulation andlor expression of a protein, providing a mechanism for the clinical observation. This study sought to investigate those polymorphisms which are most strongly associated with atypical antipsychotic induced weight gain at four levels: the ability .of the polymorphic sites to bind transcription factors, the effect ofthe polymorphisms on promoter activity in a neuroblastoma cell line, the role ofthe polymorphism in regulating 5-HT2c receptor mRNA in the human hypothalamus or hippocampus, or with mRNA and protein levels in the choroid plexus. This study finds that oligonucleotides containing either the -759 or -697 sites are capable of forming DNA-protein interactions with differential interactions at the -759C and -759T oligonucleotides. Luciferase constructs containing either the -759T or -697C alleles show reduced promoter activity, the haplotype most strongly associated with resistance to weight gain also has reduced activity. Promoter haplotypes were not significantly associated with mRNA levels in the human hippocampus, hypothalamus or mRNA and protein levels choroid plexus. Steady state mRNA and protein expression does not appear to account for resistance to weight gain but may be mediated by the loss of transcription factor binding sites manifested as diminished promoter activity in gene-reporter studies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available