Journal
PHARMACOGENOMICS
Volume 12, Issue 5, Pages 727-734Publisher
FUTURE MEDICINE LTD
DOI: 10.2217/PGS.11.16
Keywords
5-HT2C; antipsychotic; regulatory polymorphism; weight gain
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Funding
- MRC
- Grants-in-Aid for Scientific Research [23659295] Funding Source: KAKEN
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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.
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