Functional consequences of two HTR2C polymorphisms associated with antipsychotic-induced weight gain

Matthew J. Hill, Gavin P. Reynolds

    Research output: Contribution to journalArticlepeer-review

    23 Citations (Scopus)

    Abstract

    Background: Genetic variation in the promoter region of HTR2C encoding for the 5-HT2C receptor is associated with antipsychotic-induced weight gain. Several studies have investigated the regulatory potential of associated variants using gene-reporter systems. Establishing associated polymorphisms as causal variants may aid in the identification of the molecular mechanisms of phenotypic variation. Aims & methods: To this end we examined the binding of nuclear factors from rat hypothalamus to two polymorphisms in HTR2C, rs3813929 (-759C/T) and rs518147 (-697C/G) using electromobility shift assays. For rs518147, allele-specific RNA folding was also investigated. Results: Both polymorphisms bound nuclear factors, identifying the sequence fragments as regulatory elements. Importantly, rs3813929 (-759C/T) altered DNA-protein interactions with the weight gain-resistant allele abolishing the formation of two complexes. The formation of allele-specific RNA loops was also observed for rs518147. Conclusion: These data establish rs3813929 (-759C/T) as a functional polymorphism and suggest disruption of DNA-protein interactions as a mechanism by which HTR2C expression is perturbed leading to an influence on antipsychotic-induced weight gain.
    Original languageEnglish
    Pages (from-to)727 - 734
    Number of pages8
    JournalPHARMACOGENOMICS
    Volume12
    Issue number5
    DOIs
    Publication statusPublished - 2011

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