多巴胺D2受体基因与迟发性运动障碍关联研究

目的探讨DRD2基因TaqI多态性的分布与迟发性运动障碍(TD)的关联性.方法应用聚合酶链反应-限制性片段长度多态的方法,检测100例精神分裂症伴TD患者、60例无TD患者和102名正常人DRD2基因TaqI多态性,比较各组等位基因和基因型频率分布的差异.结果经吻合度检验,精神分裂症伴有TD组、无TD组和正常对照组DRD2基因各基因型的分布均符合Hardy-Weinberg平衡法则(x2=0.242,0.208,0.002,υ均=1,P均＞0.05);经比较,显示各基因型及等位基因在各组间分布无显著性差异(经Z检验,υ均=1,P均＞0.05);TD患者DRD2基因多态分布在不同性别之间无显著性差异(P＞0.05);在TD组中,基因型频数及等位基因频数与病程、服药时间、药物、剂量和AIM评分无显著性意义(P＞0.05).结论DRD2基因TaqI多态性可能与TD的发生无关联性.     

情感性精神障碍与儿茶酚邻位甲基转移酶基因的关联性研究

目的：探讨单相、双相情感性精神障碍（以下简称情感障碍）患者儿茶酚邻位甲基转移酶（COMT）基因val 108 met多态的分布，以及COMT基因与情感障碍的关联性，方法：应用聚合酶链反应－限制性片段长度多态的方法。检测203例情感障碍患者及209例正常人的COMT基因多态性，按照Hardy-Weinberg平衡法则进行吻合度检验，并采用Z检验分析COMT各基因型及等痊基因在不同组间分布的差异，结果：（1）经吻合度检验，单相抑郁症组（98例）、双相情感障碍组（104例）及正常对照组COMT各基因型的分布均符合Hardy-Weinberg平衡法则(X^2值分别为2．205，0．913，3．425，均v＝1，均P＞0．05）；（2）与正常对照组比较，单相、双相情感障碍组中COMT基因型及等位基因分布的差异均无显著性（经Z检验，均v＝1，均P＞0．05）；COMT基因各基因型及等位基因分布在不同性别的组间及组内差异亦均无显著性（P＞0．05）。结论：COMT基因val 108 met多态所在的第4外量子附近可能不存在情感障碍的易感基因。     

多巴胺D3受体基因多态性与精神分裂症患者迟发性运动障碍的关联分析

目的　观察广州地区汉族伴或不伴迟发性运动障碍 (TD)的精神分裂症患者多巴胺D3受体 (DRD3)基因Ser 9 Gly多态性分布 ,探讨DRD3基因Ser 9 Gly多态性与TD发生的关系。方法对 1 4 0例精神分裂症患者采用不自主运动评定量表 (AIMS)进行评定 ,其中 53例伴TD ,87例不伴TD。应用聚合酶链反应和限制性内切酶长度多态性方法 ,检测 1 4 0例患者的DRD3基因Ser 9 Gly多态性 ,并对DRD3各等位基因及基因型与精神分裂症患者的TD表型进行关联分析。结果　 (1 )TD组与无TD组患者基因型总体分布的差异无显著性 (χ2 =5 6 ,υ =2 ,P >0 0 5) ,等位基因频数分布的差异有显著性 (χ2 =5 1 1 ,υ =1 ,P <0 0 5)。 (2 )按性别分组后 ,在男性患者中 ,伴TD患者较不伴TD患者 1 / 1基因型和等位基因 1频率的差异有显著性 (χ2 =5 2 4 ,χ2 =5 0 6 ,P <0 0 5) ,等位基因 2的差异有显著性 (χ2 =5 0 6 ,P <0 0 5)。在女性患者中 ,DRD3各基因型及等位基因的频率的差异均无显著性 (P >0 0 5)。结论　DRD3基因Ser 9 Gly多态性可能与精神分裂症尤其是男性患者的TD关联     

COMT基因多态性与迟发性运动障碍的关联研究

目的探讨中国汉族人口中儿茶酚胺氧位甲基转移酶(COMT)基因Val108/158Met多态性与迟发性运动障碍(TD)的关系。方法以124例伴TD的精神分裂症患者(TD组)、112例不伴TD的精神分裂症患者(非TD组)及112例正常健康对照者(正常对照组)为研究对象,并采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术检测COMT基因多态性。结果(1)TD组与非TD组及正常对照组比较,等位基因及基因型频率均无统计学差异。(2)非TD组与正常对照组比较,非TD组的高活性G等位基因频率(0.78)显著高于正常对照组(0.70),低活性A等位基因频率(0.22)显著低于正常对照组(0.30);非TD组低活性A/A基因型频率(0.02)显著低于正常对照组(0.07)。(3)COMT基因型与TD严重程度具有显著相关性,A/A基因型患者的TD严重程度评分显著高于G/G基因型。结论本研究未发现COMT基因与TD的发生有关联。不伴TD的精神分裂症可能与COMT基因存在相关性,高活性G等位基因可能增加了不伴TD的精神分裂症的发生风险。COMT基因型与TD严重程度可能具有相关性,低活性A/A基因型患者可能较高活性G/G基因型患者表现更严重的TD。     

多巴胺D4受体基因多态性与海洛因依赖及渴求程度的关系

目的 探讨DRD4 exon Ⅲ 48bp可变串连重复序列（VNTR）与海洛因成瘾及线索诱发海洛因渴求程度的关系。方法 采用美国ABI公司3100基因分析仪对380名海洛因依赖者（依赖组）和275名健康对照者（对照组）的DRD4 exon Ⅲ 48bpVNTR基因多态进行检测,并给予依赖组实施线索诱发海洛因渴求实验。比较依赖组和对照组的DRD4 exon Ⅲ 48bpVNTR多态的基因型及等位基因频率是否有差异,分析不同基因型与线索诱发海洛因渴求程度的关系。结果 （1）依赖组与对照组相比．DRD4exon Ⅲ 48bpVNTR多态的基因型和等位基因频率差异均无显著性（P〉0．05）。（2）依赖组中,DRD4 exon Ⅲ 48bpVNTR长重复基因型诱发的渴求高于短重复基因型（P〈0．05）。结论 未发现DRD4 exon Ⅲ 48bpVNTR基因多态与海洛因成瘾有关,但该基因多态与线索诱发海洛因的渴求程度有关,长重复基因型线索诱发的海洛因渴求程度明显高于短重复基因型。     

5-羟色胺2A受体基因多态与海洛因成瘾及渴求程度的关联分析

目的探讨5-HT2A-1438A／G基因多态与海洛因成瘾及线索诱发海洛因渴求程度的关系。方法采 用PCR-RFLP技术对380例海洛因依赖者(依赖组)和275名健康人(对照组)的5-HT2A-1438A／G基因多态进行检 测,并对依赖组行线索诱发海洛因渴求实验。比较依赖组和对照组的5-HT2A-1438A／G多态基因型及等位基因频 率,分析依赖组不同基因型与线索诱发海洛因渴求程度和主观戒断反应的关系。结果 (1)依赖组与对照组的5- HT2A-1438A／G的基因型和等位基因频率均无显著性差异(P>0．05)。(2)依赖组中,5-HT2A-1438A／G的3种多态 基因型诱发渴求和主观戒断反应的差异有统计学意义(P<0．05),G／G基因型诱发渴求和主观戒断反应均小于A／ A(P=0．024,P=0．009)和A／G(P=0．018,P=0．011)基因型。结论未发现5-HT2A-1438A／G基因多态与海洛 因成瘾有关,但该基因多态性与线索诱发海洛因的渴求程度有关,A+(A／A和A／G)携带者线索诱发海洛因的渴求 程度和主观戒断反应明显高于A-(G／G)携带者。     

多巴胺转运体基因多态性与Tourette综合征疗效的相关性研究

目的 探讨不同疗效的Tourette综合征(TS)患者多巴胺转运体(DAT1)基因40 bp可变串联重复序列(VNTR)多态性分布频率是否存在差异.方法 应用聚合酶链反应-可变串联重复序列多态性分析技术,检测普通TS组(52例)、难治性TS组(63例)和正常对照组(57例)DAT1基因40 bp VNTR多态性;根据自制的临床资料调查表和耶鲁综合抽动严重程度量表(YGTSS)收集患者临床资料,使用美国精神障碍诊断与统计手册第4版(DSM-Ⅳ)Tourette综合征诊断标准进行诊断.结果 正常对照组、普通TS组和难治性TS组DAT1基因40 bp VNTR基因型频率分布差异无统计学意义(χ2=12.638,P=0.125);难治性TS组等位基因440 bp频率为8,高于普通TS组及正常对照组(1、0),但差异无统计学意义(χ2=11.352,P=0.053).结论 难治性TS中DAT1基因40 bp VNTR 440 bp等位基因出现频率较高,普通TS与难治性TS遗传机制可能存在差异,但需扩大样本含量进一步验证.

Abstract：

Objective To study the difference of dopamine transporter ( DAT1 )gene 40 bp variable number of tandem repeat ( VNTR ) genotype and allele frequency in TS patients with different curative effect in Chinese Han population. Methods In this study, the 40 bp polymorphism in the DAT1 gene was analyzed by using polymerase chain reaction-variable number of tandem repeat and polymorphism. The clinical data and tic symptoms was assessed with the clinical data schedule table and the Yale Global Tic Severity Scale ( YGTSS ). TS was diagnosed with the Diagnostic and Statistical Manual of Mental Disorders,the Forth Edition( DSM-Ⅳ )diagnostic criteria for Tourette syndrome. Results There was no significant differences in the frequencies of genotype for DAT1 gene 40 bp VNTR between normal controls ( 57 samples )and common TS children ( 52 samples ) and refractory TS children ( 63 samples ) (χ2 = 12. 638, P =0.125).The allele 440bp tended to be more in children with refractory TS(refractory TS:commmon TS:normal controls=8:1:0),but with no significat differences(χ2=11.352,P=0.053).Conclusions The DAT1 gene 40 bp VNTR 440 bp allele frequency seems to be higher in children with refractory TS,which suggests common TS and refractory TS have different genetic background. It should be verified by making larger samples in future study.     

广州市阿尔茨海默病人及正常老人丁酰胆碱酯酶基因K变异对照研究

目的　观察丁酰胆碱酯酶基因 (BCHE)K变异在广州地区汉族老年人中的分布 ,探讨其与晚发阿尔茨海默病 (AD)的关联性。方法　以 10 6例晚发AD患者和 133名健康老年人为对象进行病例 对照研究。采用等位基因特异聚合酶链反应法 (AS PCR)分析BCHE基因K型多态性。结果　晚发AD患者和正常老年人中 ,正常等位基因 1的频率分别为 93 4 0 %和 93 6 1% ,K变异等位基因 2的频率分别为 6 6 0 %和 6 39% ;晚发AD患者和正常老年人之间BCHE基因K多态各等位基因和基因型分布差异无显著性 (P >0 0 5 ) ;样本采用载脂蛋白Eε4基因 (APOEε4 )分层后 ,AD组与对照组BCHE基因K变异频率仍然无显著性差异 (P >0 0 5 )。结论　BEHE K变异在广州地区汉族人群中与晚发AD不存在关联 ,提示该多态性不是晚发AD的风险因子。     

儿茶酚胺氧甲基转移酶基因rs4680位点多态性与强迫症的关联研究

目的:探讨儿茶酚胺氧甲基转移酶(COMT)基因多态性(rs4680)与强迫症的关联性。方法:以山东汉族人群中的400例强迫症患者和459名健康对照者为研究对象,按性别、发病年龄分层,采用MassARRAY飞行时间质谱(MALDI-TOF)技术对COMT基因单核苷酸多态性(SNP)位点rs4680进行基因分型,比较各组等位基因、基因型频率。结果:COMT rs4680位点等位基因和基因型频率在强迫症组和对照组分布差异无统计学意义(P 0. 05)。按性别、发病年龄分层后,各强迫症组和对照组该位点等位基因和基因型频率分布差异也无统计学意义(P 0. 05)。结论:COMT基因多态性(rs4680)与强迫症可能不存在关联。     

单胺氧化酶B基因微卫星多态与帕金森病的相关分析

目的 研究上海地区汉族人群中单胺氧化酶B(MAOB)基因第二内含子中鸟嘌呤、胸腺嘧啶(GT)二碱基重复的微卫星多态位点与帕金森病(Parkinson’s disease，PD)易患性之间的关系。方法 采用扩增片段长度多态法(Amp—FLP)，在上海汉族人群中选择67例散发PD患者为PD组和204名健康者为对照组，运用微卫星荧光标记—半自动基因分型技术精确计算出微卫星等位基因片段大小，进而分析该多态在PD易患性中的作用。结果 该位点短片段(≤170bp)等位基因的分布在：PD组中明显高于与对照组(x^2=11．28，P=0．001)，而172bp等位基因在PD组中亦明显低于与对照组(x^2=5．16，P=0．023)。结论 MAOB基因GT二碱基重复多态位点与本组PD患者的易患性有关。     

5-HT2A受体基因T102C遗传多态性与迟发性运动障碍的关联研究

目的探讨广东地区汉族人群中5HT2A受体基因T102C多态性的分布与迟发性运动障碍（TD）的关联性。方法采用病例-对照研究。应用聚合酶链反应-限制性片段长度多态性（PCR—RFLP）方法，检测65例伴有TD和59倒无TD的精神分裂症患者5HT2A受体基因T102C多态性分布，比较两组间基因型和等位基因频率的差异。结果经x^2检验，T102C基因型与等位基因频率在两组问未见显著性差异（P〉0．05）。结论本研究中未发现广东地区汉族人群中5～HT2A受体基因T102C多态性与迟发性运动障碍存在关联。     

No association between the brain-derived neurotrophic factor gene Val66Met polymorphism and tardive dyskinesia in schizophrenic patients

OBJECTIVE: This study investigated whether the brain-derived neurotrophic factor (BDNF) gene Val66Met single-nucleotide polymorphism (SNP) is associated with antipsychotic-induced tardive dyskinesia (TD) in schizophrenia. METHODS: Genotyping was performed for the BDNF gene Val66Met SNP in Korean schizophrenic patients with (n=83) and without TD (n=126) who were matched for antipsychotic drug exposure and other relevant variables. RESULTS: The frequencies of genotypes (chi2=2.37, p=0.306) and alleles (chi2=0.03, p=0.867) did not differ significantly between these two groups. CONCLUSION: These findings suggest that the BDNF polymorphism does not play a major role in the susceptibility to TD in schizophrenic patients.     

Genetic association analysis of the glutathione peroxidase (GPX1) gene polymorphism (Pro197Leu) with tardive dyskinesia

A possible involvement of oxidative stress in the pathophysiology of tardive dyskinesia (TD) has previously been proposed (reviewed in [Andreassen, O.A., Jorgensen, H.A., 2000. Neurotoxicity associated with neuroleptic-induced oral dyskinesias in rats. Implications for tardive dyskinesia? Progress in Neurobiology 61, 525-541.]). Long-term administration of neuroleptics alters dopaminergic turnover, which results in increased formation of reactive oxygen species (ROS). This is hypothesized to lead to TD through neuronal toxicity as a consequence of oxidative stress. In the present study, the relationship between TD and a possible functional polymorphism of the human glutathione peroxidase (GPX1) gene (an important antioxidant enzyme) was studied in 68 chronic treatment-refractory patients with schizophrenia. A proline (Pro) to leucine (Leu) substitution at codon 197 (Pro197Leu) in the GPX1 gene was genotyped. No significant difference in total Abnormal Involuntary Movements Scale (AIMS) scores was observed among patients in the three genotype groups. Moreover, no significant differences in genotype or allele frequencies were observed between subjects with and without TD. Our results suggest that the GPX1 gene polymorphism does not confer increased susceptibility to TD, although further studies are warranted before a conclusion can be drawn.     

多巴胺D2受体基因的TaqI A多态性与迟发性运动障碍的关联分析

目的　研究多巴胺D2受体 (DRD2 )基因TaqIA多态性与精神分裂症伴迟发性运动障碍 (TD)的相关性。方法　使用异常不自主运动量表 (AIMS)评定精神分裂症患者有无TD及TD严重程度 ,并采用简明精神病评定量表 (BPRS)评定患者精神症状 ;应用聚合酶链反应 (PCR)—限制性片段长度多态性 (RFLP)法分析TD组和非TD组的DRD2基因的TaqIA等位基因频率和基因型分布。结果　DRD2基因TaqIA的等位基因频率和基因型分布在TD组与非TD组之间均无显著性差异 ,且不同基因型间的AIMS总分值也无显著性差异。结论　在中国汉族男性精神分裂症患者中DRD2基因的TaqIA多态性可能不是影响TD发生的主要危险因素。     

Cytochrome P450 2D6 genotyping and association with tardive dyskinesia in Chinese schizophrenic patients.

BACKGROUND: The discovery of Cytochrome P450 2D6 (CYP 2D6) polymorphism is implicated in individual differences in drug metabolism rate. Mutation with defective alleles is associated with reduced metabolism of many anti-psychotic drugs metabolized by CYP 2D6. This may contribute to the development of tardive dyskinesia (TD) in patients with prolonged exposure to anti-psychotic drugs. METHODS: In this controlled study, the genotype of CYP 2D6*10 alleles, movement disorders and clinical characteristics in 38 Chinese schizophrenic patients with TD were compared with 38 age- and sex-matched schizophrenia patients without TD. RESULTS: There was no significant correlation between CYP 2D6*10 genotypes and TD in men. However, a significant increase in the frequency of CYP 2D6*10 allele was found in female patients with TD. CONCLUSIONS: The sex differences in CYP 2D6 genotyping and vulnerability to develop TD suggest that a biological predisposition that affects pharmacokinetics may be more significant in women, whereas other factors may be more important in men.     

Genetic association analysis of 5-HT(6) receptor gene polymorphism (267C/T) with tardive dyskinesia

Possible involvement of serotonergic (5-hydroxytryptamine: 5-HT) receptors in the pathophysiology of tardive dyskinesia (TD) has been suggested. In the present study, the relationship between the 5-HT(6) receptor gene (HTR6) polymorphisms and TD was studied in 173 Japanese patients with schizophrenia. The 267C/T allele of HTR6 was genotyped using PCR amplification followed by endonuclease digestion. The patients with the three 267C/T genotypes showed no significant difference in gender, age, duration of illness, or current antipsychotic dose. In addition, there were no significant differences in total AIMS scores among patients with the three genotypes. Moreover, no significant differences in genotypes and allele frequencies were observed between subjects with and without TD. These results suggest that the 267C/T polymorphism of HTR6 does not confer increased susceptibility to TD.     

Genetic association of BDNF val66met and GSK-3β-50T/C polymorphisms with tardive dyskinesia

Aims:  Neurodegenerative processes may be involved in the pathogenesis of tardive dyskinesia (TD), and a growing body of evidence suggests that brain-derived neurotrophic factor (BDNF) plays a role in both the antipsychotic effects and the pathogenesis of TD. BDNF and glycogen synthase kinase (GSK)-3β are important in neuronal survival, and thus abnormal regulation of BDNF and GSK-3β may contribute to TD pathophysiology. This study investigated the relationship between two polymorphisms, val66met in the BDNF coding region and -50T/C in the GSK-3β promoter, and susceptibility to TD among a matched sample of patients having schizophrenia with TD ( n  = 83), patients with schizophrenia without TD ( n  = 78), and normal control subjects ( n  = 93).
Methods:  All subjects were Korean. The BDNF val66met and GSK-3β-50T/C genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism analyses.
Results:  Polymerase chain reaction analysis revealed no significant difference in the occurrence of the polymorphisms among the TD, non-TD, and control subjects, but a significant interaction was observed among the groups possessing BDNF val allele in compound genotypes ( P  = 0.001). We found that the schizophrenic subjects with the C/C GSK-3β genotype, who carry the val allele of the BDNF gene, are expected to have a decreased risk of developing neuroleptic-induced tardive dyskinesia ( P  < 0.001).
Conclusions:  Our results demonstrate that the GSK-3β C/C genotype with the BDNF val allele is associated with patients having schizophrenia without TD. This study also suggests that the BDNF and GSK-3β gene polymorphisms work in combination, but not individually, in predisposing patients with schizophrenia to TD.     

Apolipoprotein E epsilon4 and tardive dyskinesia in a Japanese population

The findings that free radicals play a causative role in the occurrence of tardive dyskinesia (TD) and that apolipoprotein E (ApoE) 4 has decreased anti-oxidant activity suggest a potential link between TD and ApoE alleles. We, therefore, examined ApoE allelic frequencies in schizophrenic subjects with TD and non-TD. Serum samples were obtained from 333 DSM IV-diagnosed schizophrenic patients and 191 controls in Japan. The presence of TD was evaluated by research diagnostic criteria for TD. ApoE phenotypes of the serum samples were determined by polyacrylamide gel isoelectricfocusing. A total of 62 TD subjects (31 males, 31 females) were identified among all patients examined. No significant differences in ApoE allelic frequency were found between TD and non-TD groups. ApoE epsilon4 allele frequency, however, was significantly lower in the female TD group than in the male TD group. These findings do not clearly demonstrate a certain association between TD and the epsilon4 allele, but may preliminarily reveal a difference in influence of this allele on the development of TD between males and females.     

Susceptibility to neuroleptic-induced tardive dyskinesia and the T102C polymorphism in the serotonin type 2A receptor.

BACKGROUND: Genetic factors have been implicated in the pathophysiology of the movement disorder tardive dyskinesia, which may involve dopamine-serotonin interaction. Case-control association studies have identified the T102C polymorphism of the 5-HT2A receptor gene as being associated with schizophrenia and responsiveness to clozapine. In this study, we examine the association of this polymorphism in the 5-HT2A receptor gene as a risk factor for developing schizophrenia and tardive dyskinesia from prolonged treatment with neuroleptics. METHODS: Ninety-seven healthy control subjects with no history of mental illness and 221 schizophrenic patients (87 with tardive dyskinesia, 134 without) were genotyped by PCR-RFLP. RESULTS: Comparison between cases and control subjects revealed no significant association between the C allele and schizophrenia. There was significant difference in allele frequency (p = .044, OR = 1.54 95% CI = 1.02-2.33) between patients who developed tardive dyskinesia and those who did not. Significant difference remains even after adjusting for age and neuroleptic dosage (p = .041) with the odds ratio at 1.64 (95% CI = 1.02-2.62). CONCLUSIONS: A genetic variant of the 5-HT2A receptor may be associated with neuroleptic-induced tardive dyskinesia in schizophrenia. Further studies are needed to replicate the finding. The role of 5-HT2A receptor in the etiology of tardive dyskinesia or treatment-resistant schizophrenia should be further investigated.