Lack of association between serotonin-2A receptor gene (HTR2A) polymorphisms and tardive dyskinesia in schizophrenia
Lack of association between serotonin-2A receptor gene (HTR2A) polymorphisms and tardive dyskinesia in schizophrenia
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DOI：
10.1038/sj.mp.4000847
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发表时间：
2001-03-01
影响因子：
11
通讯作者：
Kennedy, JL
中科院分区：
文献类型：
--
作者：
Basile, VS;Ozdemir, V;Kennedy, JL
迟发性运动障碍(TD)是一种与长期使用典型抗精神病药物治疗有关的致残性神经副作用。家系研究和动物模型为TD的遗传易感性提供了证据。新的非典型抗精神病药物对TN的风险最小，部分原因是它们能够阻断5-HT2A(5-HT2A)受体。在基底节也发现了5-HT2A受体，这是一个在抗精神病药物诱导的运动障碍中发挥关键作用的大脑区域。我们检测了5-HT2A受体基因(HTR2A)变异与TN表型的关系。对136例典型抗精神病药物治疗和DSM-IIIR诊断为精神分裂症的难治性或耐受性精神分裂症患者进行了HTR2A基因3个多态性的研究，其中一个是沉默(C102T)，一个是氨基酸序列改变(His452tyr)，一个是启动子区域(A-1437G)。我们未发现伴与不伴TD患者之间HTR2A基因多态的等位基因、基因型或单倍型频率有显著差异(P>；0.05)。使用ANCOVA统计和TD表型(异常不自主运动量表(AIMS)评分)的连续测量进一步分析发现，尽管控制了潜在的混杂因素，如年龄、性别和种族，但AIMS评分并未受到HTR2A基因多态性的显著影响(P>；0.05)。从理论上讲，中枢5-羟色胺能功能可以在不同的其他机制水平上受到遗传控制，包括5-羟色胺合成速率(色氨酸羟基酶基因)、释放、重摄取(5-羟色胺转运体基因)和降解(单胺氧化酶基因)。对这些其他5-羟色胺能基因的分析表明，总的来说，HTR2A基因的多态似乎不会影响TD的风险。进一步研究评估与5-羟色胺能系统相关的多个候选基因是有必要的，以剖析复杂TD表型的遗传基础。
Tardive dyskinesia (TD) is a disabling neurological side effect associated with long-term treatment with typical antipsychotics. Family studies and animal models lend evidence for hereditary predisposition to TD. The newer atypical antipsychotics pose a minimal risk for Tn which is in part attributed to their ability to block the serotonin-2A (5-HT2A) receptor. 5-HT2A receptors were also identified in the basal ganglia; a brain region that plays a critical role In antipsychotic-induced movement disorders. We tested the significance of variation in the 5-HT2A receptor gene (HTR2A) in relation to the Tn phenotype. Three polymorphisms in HTR2A, one silent (C102T), one that alters the amino acid sequence (his452tyr) and one in the promoter region (A-1437G) were investigated in 136 patients refractory or intolerant to treatment with typical antipsychotics and with a DSM-IIIR diagnosis of schizophrenia. We did not find any significant difference in allele, genotype or haplotype frequencies of polymorphisms in HTR2A among patients with or without TD (P > 0.05). Further analysis using the ANCOVA statistic with a continuous measure of the TD phenotype (Abnormal involuntary Movement Scale (AIMS) score) found that the AIMS scores were not significantly influenced by HTR2A polymorphisms, despite controlling for potential confounders such as age, gender and ethnicity (P > 0.05). Theoretically, central serotonergic function can be subject to genetic control at various other mechanistic levels including the rate of serotonin synthesis (tryptophane hydroxylase gene), release, reuptake (serotonin transporter gene) and degradation (monoamine oxidase gene). Analyses of these other serotonergic genes are indicated, In summary, polymorphisms in HTR2A do not appear to influence the risk for TD. Further studies evaluating in tandem multiple candidate genes relevant for the serotonergic system are warranted to dissect the genetic basis of the complex TD phenotype.