传统抗精神病药物所致迟发性运动障碍的药理遗传学初步研究

Pharmacogenetic assessment of antipsychotic induced tardive dyskinesia: contribution of 5-hydroxytryptamine 2C receptor gene and of a combination of dopamine D3 variant allele (Gly) and MnSOD wild allele (Val)

目的 进一步探讨多巴胺D2、D3受体 (dopamineD2 ,D3receptor ,DRD2 ,DRD3 )功能基因多态性与迟发性运动障碍 (tardivedyskinesia ,TD)的相关性及各候选基因 ,同时包括五羟色胺 2C受体 ( 5 hy droxytryptamine 2Creceptor ,HTR2C)和锰超氧化物歧化酶 (manganesesuperoxidedismutase ,MnSOD)基因的相互作用对TD发生的影响。方法 使用异常不自主运动量表 (abnormalinvoluntarymovementscale ,AIMS)评定精神分裂症 (schizophrenia ,SCH)患者有无TD及其严重程度 ,并采用简明精神病评定量表评定患者精神症状 ;应用聚合酶链反应 限制性片段长度多态性技术分析TD组和非TD组各候选基因等位基因和 (或 )基因型分布频率及其结合分布频率 ,并分析对AIMS总分值的影响。结果 各候选基因在SCH患者组以及TD和非TD组基因型分布均符合Hardy Weinberg平衡定律 ;TD组HTR2C基因 697C(突变型 )等位基因频率高于非TD组 ,差异有显著性 (P <0 .0 5 ) ;DRD2基因TaqⅠA1/A2、DRD3基因Ser9Gly和Mn SOD基因Ala 9Val等位基因频率和基因型分布在TD组与非TD组之间差异均无显著性 (P >0 .0 5 ) ;仅DRD3突变型 (Gly)和MnSOD野生型 (Val)结合分布频率高于其它结合型 ,差异有显著性 (P <0 .0 5 ) ;但上述各候选基因不同等位基因和

Objective: To further investigate whether, the functional polymorphisms of dopamine D2 receptor (DRD2) and dopamine D3 receptor (DRD3) genes associate with the development of tardive dyskinesia (TD) in schizophrenia, and whether the interactive effects of DRD2, DRD3, 5-hydroxytryptamine 2C receptor (HTR2C) and manganese superoxide dismutase (MnSOD) genes contribute to the severity of TD. Methods: The patients with schizophrenia were assessed for TD by the Abnormal Involuntary Movement Scale (AIMS). Eventually, 42 schizophrenics with persistent TD were in the TD group, and 59 schizophrenics without TD were in the non-TD group. The polymorphism of each candidate gene was analyzed using a polymerase chain reaction-based restriction fragment length polymorphism analysis. Results: The genotype distributions of the candidate genes in the groups were all consistent with the Hardy-Weinberg equilibrium. Allele frequencies for -759C/T and -697G/C polymorphisms in HTR2C gene showed a significant excess of -697 variant (P0. 05). Interestingly, as compared with the other joint allelic types, a significant excess of carrying both DRD3 variant allele (Gly) and MnSOD wild allele (Val) was found in the TD group (P<0. 05). However, neither the allele and genotypes nor the clinical demographic characteristics contributed to the higher total AIMS scores in the patients of the TD group. There were no significant differences in any of the clinical demographic characteristics between the subgroups of any genotype in TD and non-TD groups. Conclusion: The excess of -697 variant in the promoter regulation region of the HTR2C gene may be a risk factor for the susceptibility to the occurrence of TD in Chinese male patients with schizophrenia. A combination of DRD3 variant allele (Gly) and MnSOD wild allele (Val) may increase the susceptibility to the development of TD.