Division of Psychiatry & Neuroscience, Queen's University Belfast, Whitla Medical Building, 97 Lisburn Road, Belfast BT97BL, UK.
Pharmacogenomics. 2011 May;12(5):727-34. doi: 10.2217/pgs.11.16. Epub 2011 Mar 11.
Genetic variation in the promoter region of HTR2C encoding for the 5-HT(2C) 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.
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.
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.
5-羟色胺（5-HT）2C 受体编码基因启动子区域的遗传变异与抗精神病药引起的体重增加有关。已有多项研究使用基因报告系统探讨了相关变异的调控潜能。确定相关多态性是否为因果变异有助于阐明表型变异的分子机制。
为此，我们使用电泳迁移率变动分析检测了大鼠下丘脑核因子与 HTR2C 中的两个多态性 rs3813929（-759C/T）和 rs518147（-697C/G）的结合情况。对于 rs518147，还研究了等位基因特异性 RNA 折叠情况。
这两种多态性都结合了核因子，确定了这些序列片段为调控元件。重要的是，rs3813929（-759C/T）改变了与体重增加抵抗等位基因的 DNA-蛋白相互作用，从而阻止了两个复合物的形成。对于 rs518147，也观察到了等位基因特异性 RNA 环的形成。
这些数据将 rs3813929（-759C/T）确立为功能性多态性，并提示 DNA-蛋白相互作用的破坏可能是 HTR2C 表达受到干扰从而影响抗精神病药引起的体重增加的机制之一。
