烟碱型乙酰胆碱受体基因多态与早发性精神分裂症的关联研究

目的探讨烟碱型乙酰胆碱受体基因多态在早发性精神分裂症发生中的作用。方法采用TaqMan荧光探针基因分型技术对421例早发性精神分裂症患者和598例健康对照者的α3、α4、α7、α5烟碱型乙酰胆碱受体基因(nicotinic acetylcholine receptor subunit gene)即CHRNA3(rs1317286)、CHRNA4(rs1044396)、CHRNA7(rs6494212)及CHRNA5(rs16969968,rs684513)基因多态位点进行基因分型,分析这些位点与早发性精神分裂症的关联及其与发病年龄的关系,并进一步分析基因与基因的交互作用。结果单位点分析显示所有位点的差异比较结果无统计学意义。Kaplan-Meier生存分析显示携带rs1317286G等位基因的患者发病年龄晚于不携带rs1317286G等位基因的患者[发病年龄分别为(15.5±0.33)岁和(15.1±0.14)岁,P=0.010]。CHRNA5基因的两个单核苷酸多态位点(single nucleotide polymorphisms,SNPs)组成的单体型也显示不与早发性精神分裂症关联。进一步的基因交互作用分析显示rs1044396、rs6494212及rs684513联合作用模式可能与精神分裂症相关(P=0.0007)。结论 CHRNA3(rs1317286)位点可能与精神分裂症的发病年龄相关;rs1044396、rs6494212及rs684513基因的联合作用模式可能与早发性精神分裂症有关。     

精神分裂症伴发2型糖尿病与色氨酸羟化酶基因多态性关联研究

目的：在中国汉族精神分裂症患者中探讨色氨酸羟化酶（TPH）基因A218C（rs1800532）多态性与2型糖尿病共病的关联性。方法：采用聚合酶链反应-限制性片断长度多态（PCR-RFLP）技术在中国汉族人群中对98例伴发2型糖尿病的精神分裂症患者（伴糖尿病组）及109例单纯精神分裂症患者（不伴糖尿病组）进行TPH基因A218C的分型,并进行等位基因及基因型比较。结果：伴糖尿病组与不伴糖尿病组比较,TPH6基因A218C多态性等位基因分布（χ^2=0．00,df=1,P〉0．05）和基因型分布（χ^2=3．78,df=2,P〉0．05）均无显著差异。在男性患者中,伴糖尿病组与不伴糖尿病组基因型分布存在显著差异（χ^2=6．57,df=2,P=0．037）,而等位基因分布（χ^2=1．28,df=1,P=0．26）则无明显差异;在女性患者组中,伴糖尿病组与不伴糖尿病组基因型分布（χ^2=1．54,df=2,P=0．46）和等位基因分布（χ^2=0．02,df=1,P〉0．05）均无显著差异。结论：在中国汉族男性精神分裂症患者中TPH基因A218C多态性与患2型糖尿病存在关联,其可能是男性精神分裂症患者患2型糖尿病的易感基因。     

α7-烟碱样乙酰胆碱受体基因rs1042724多态性与精神分裂症的关联研究

目的研究α7-烟碱样乙酰胆碱受体基因rs1042724多态性与精神分裂症的相关性。方法运用聚合酶链反应扩增及单核苷酸多态性的分子生物学技术,对符合精神分裂症诊断标准的98个先证者及其父母组成的核心家系,测定α7-烟碱样乙酰胆碱受体基因分型,进行精神分裂症的α7-烟碱样乙酰胆碱受体基因多态性的关联分析和传递不平衡(TDT)检验。结果TDT检验结果提示α7-烟碱样乙酰胆碱受体基因等位基因与精神分裂症之间的相关性(McNemarχ2=4.21,P<0.05),且等位基因T携带者,其精神分裂症的易患性是C携带者的1.31倍(RR=1.31,χ2(RR)=3.96,P<0.05)。结论提示α7-烟碱样乙酰胆碱受体基因rs1042724与精神分裂症相关联。     

α7-烟碱样乙酰胆碱受体基因多态性与精神分裂症的关联研究

目的 研究α7-熘碱样乙酰胆碱受体基因rs1042724多态性与精神分裂症的相关性。方法运用聚合酶链反应扩增及单核苷酸多态性的分子生物学技术，对符合精神分裂症诊断标准的98个先证者及其父母组成的核心家系，测定α7-烟碱样乙酰胆碱受体基因分型，进行精神分裂症的α7-烟碱样乙酰胆碱受体基因多态性的关联分析和传递不平衡（TDT）检验。结果TDT检验结果提示α7-烟碱样乙酰胆碱受体基因等位基因与精神分裂症之间的相关性（McNemarX^2=4．21，P〈0．05），且等位基因T携带者，其精神分裂症的易患性是C携带者的1．31倍（RR=1．31,X^2（RR）=3．96，P〈0．05）。结论 提示α7-烟碱样乙酰胆碱受体基因rs1042724与精神分裂症相关联。     

神经型烟碱乙酰胆碱受体α7亚单位基因和儿茶酚-O-甲基转移酶基因多态性与精神分裂症的关联研究

目的 探讨CHRNA7、COMT基因多态性与精神分裂症的相关关系.方法 采用聚合酶链反应及聚丙烯酰胺凝胶芯片技术,检测粤东地区精神分裂症患者(140例)与正常对照者(100例)CHRNA7基因3个单核苷酸多态性位点(rs2337980、rs 1909884、rs883473)和COMT基因3个单核苷酸多态性位点(rs4680、rs737865、rs165599),并对分型结果进行测序鉴定.结果 所有位点的单核苷多态性与精神分裂症发病风险无关联(均P＞0.05).结论 在中国粤东地区CHRNA7基因3个位点(rs2337980、rs 1909884、rs883473)和COMT基因3个位点(rs4680、rs737865、rs165599)的基因多态性可能与精神分裂症无关,但此结论尚需要进一步扩大样本量进行验证.     

精神分裂症与5—HT2A受体基因相关联

目的：探讨中国汉族人群精神分裂症与5－HT2A受体基因T102C多态性之间的关系。方法：选择精神分裂症患者286例,按病期分一般组和慢性组;以291例正常人对照,也按现年龄相应地分为一般对照组和慢性对照组,分生物学技术采用PCR扩增及MSPI内切酶酶切技术,检测各组研究对象的5－HT2A受体基因的基因型和等位基因的频率分布,结果：一般组精神分裂症患者5－HT2A受体基因A2／A2型频率及A2等位基因频率均显著高于对照组（ZA2／A2＝2．97,P＜0．05;ZA2＝2．19,P＜0．05）。经关联分析,其OR值分别为2．35（P＜0．05）和1．45（P＜0．05）。结论：提示中国汉族人群中5－HT2A受体基因多态性可能与精神分裂症呈正关联,而与慢性精神分裂症无关联。     

精神分裂症与5HT2a受体基因GT102C多态性的关联研究

目的 探讨汉族人５－ＨＴ２ａ受体基因Ｔ１０２Ｃ多态性与精神分裂症病因之间的关系。方法 取２２３例精神分裂症病人作研究，以１６２例正常人作对照，用聚合酶链式反应扩增及内切酶酶切技术测定所研究对象的基因型和等位基因。结果 发现精神分裂症与５－ＨＴ２ａ受体基因的基因型Ａ１／Ａ１关联。结论 ５－ＨＴ２ａ受体基因Ｔ１０２Ｃ多态性与精神分裂症的易感性有关，基因型Ａ１／Ａ１是精神分裂症的风险因子。     

色氨酸羟化酶基因多态性与精神分裂症的关联研究

目的探讨中国汉族人群色氨酸羟化酶(TPH)基因A218C多态性与精神分裂症的关系。方法选取符合美国精神障碍诊断与统计手册第4版(DSM-IV)精神分裂症诊断标准的患者212例和正常对照168名,应用聚合酶链式反应(PCR)扩增及限制性片段长度多态性(RFLP)技术检测TPH基因A218C多态性,比较两组基因型和等位基因频率。结果TPH基因的A218C多态性基因型和等位基因频数在患者组与对照组间的分布差异无统计学意义(P>0.05)。②女性患者等位基因A频率显著高于女性对照组(χ2=4.905,P=0.027,OR=1.637,95%CI:1.057~2.536)。③早发型与晚发型分裂症间基因型和等位基因频率的差异无统计学意义(P>0.05)。④患者组家族史阴性和阳性亚组间的A218C多态性的基因型和等位基因频率的差异无统计学意义(P>0.05)。结论TPH基因A218C多态性等位基因A可能是女性精神分裂症的危险因子。     

精神分裂症与5HT2a受体基因T102C多态性的关联研究

目的 探讨汉族人5-HT2a受体基因T102C多态性与精神分裂症病因之间的关系。方法 取223例精神分裂症病人作研究,以162例正常人作对照。用聚合酶链式反应(PCR)扩增及内切酶酶切技术测定所研究对象的基因型和等位基因。结果 发现精神分裂症与5-HT2a受体基因的基因型A1/A1关联。结论 5-HT2a受体基因T102C多态性与精神分裂症的易感性有关,基因型A1/A1是精神分裂症的风险因子。     

5-羟色胺2A受体基因多态性与精神分裂症的相关性研究

目的探讨５－羟色胺２Ａ受体基因多态性与精神分裂症的相关性。方法采用Ａｍｐ－ＲＦＬＰ方法对精神分裂症患者和各对照组的５－羟色胺２Ａ受体（简称５－ＨＴ２ＡＲ）基因的相关性进行了研究。结果精神分裂症患者５－ＨＴ２ＡＲ基因Ａ２Ａ２纯合子基因型频率及等位基因Ａ２频率均高于对照组（χ２＝８．９９，８３８Ｐ均＜０．０１），对发生精神分裂症的５－ＨＴ２ＡＲ基因Ａ２Ａ２纯合子相对危险度是２３６。结论本实验结果提示５－ＨＴ２ＡＲ基因的变异与精神分裂症有密切相关性。     

Direct actions of anticholinesterases on the neuronal nicotinic acetylcholine receptor channels

Recent studies have suggested that anticholinesterases including organophosphates and carbamates act directly on the nicotinic acetylcholine receptor (AChR) channel. We performed whole-cell and single-channel patch-clamp experiments to elucidate the mechanism of action of anticholinesterases on the nicotinic AChR in rat clonal phaeochromocytoma (PC12) cells. Neostigmine and carbaryl showed a biphasic effect; enhancement and suppression of carbachol-induced whole-cell currents. The currents induced by 100 μM carbachol was enhanced by the first co-application with 10 or 100 μM neostigmine, and the current was eventually suppressed below the control level during repeated co-applications. The decay phase of current was accelerated by neostigmine. Carbaryl at 0.1 μM greatly potentiated the carbachol-induced current, and at higher concentrations (0.3–3 μM), current was suppressed. In single-channel experiments, these compounds increased the short closures or gaps during channel opening without changing the single-channel conductance. Mean open time and burst duration were decreased in the presence of neostigmine and carbaryl. These results indicate that neostigmine and carbaryl directly block the nicotinic AChR channel.     

Lead modulation of the neuronal nicotinic acetylcholine receptor in PC12 cells

Lead is known to modulate several ligand- and voltage-gated ion channels, including the nicotinic acetylcholine receptor (AChR) channel. We examined the effects of lead on the nicotinic AChR in rat clonal phaeochromocytoma PC12 cells using whole-cell and single-channel patch-clamp techniques to clarify the detailed mechanism of action. Lead suppressed acetylcholine-induced currents in a dose-dependent manner with an EC₅₀ value of 37 μM and a Hill coefficient of 0.82. At the single-channel level, 1–10 μM lead shortened the opening and burst durations, and increased the duration of mean closed time. The open probability was significantly decreased by lead. These changes of single-channel kinetics result in a significant decrease in the total charge carried through the open AChR channels explaining the suppressive effect of lead on acetylcholine-induced whole-cell currents. © 1997 Elsevier Science B.V. All rights reserved.     

RELN基因rs12705169位点与女性偏执型精神分裂症关联

目的以中国汉族偏执型精神分裂症患者为研究对象,重复验证RELN(Reelin)基因单核苷酸多态性与精神分裂症的关联性。方法以美国精神障碍诊断与统计手册第四版为诊断标准(Diagnostic and StatisticalManual of Mental Disorders-Fourth Edition,DSM-Ⅳ)在河南省北部地区收集326例偏执型精神分裂症患者(男女各半),在同一地域招募健康体检者334名(男女各半)作为对照,检测RELN基因rs12705169、rs11764507和rs17157643单核苷酸多态性位点。结果仅发现患者组和对照组之间rs12705169位点的基因型和等位基因频率差异有统计学意义(P<0.01)。按性别分层后进一步分析,rs12705169在女性患者和对照之间基因型和基因频率分布差异具有统计学意义(CC:OR=0.27,95%CI=0.18～0.45;AC:OR=0.43,95%CI=0.29～0.63,P<0.01)。结论RELN基因多态性与中国女性偏执型汉族精神分裂症存在关联,RELN基因可能是精神分裂症的易感基因。     

D4受体基因与精神分裂症的关联研究

目的 探讨上海地区汉族人D4受体基因与精神分裂症的易感性、患者的性别、发病年龄、家族史以及症状严重度之间的关系。方法 抽取38例精神分裂症病人作研究,以76例正常人作对照。用聚合酶链式反应（PCR）扩增技术测定所有研究对象的D4基因型和等位基因。结果 发现D4受体基因与精神分裂症的易感性相关联,而与患者的性别、发病年龄、家族史以及症状严重度均无关联;发现正常对照组D4受体基因与性别相关联。结论 D4受体基因可影响精神分裂症患者的易感性,但不改变患者的发病年龄以及症状严重度,D4受体基因多态性的频率分布不受患者的性别及家族聚集性的影响;正常人群中D4受体基因多态性的频率分布存在性别差异。     

Lower core body temperature and attenuated nicotine-induced hypothermic response in mice lacking the beta4 neuronal nicotinic acetylcholine receptor subunit

Diverse physiological and pathological effects of nicotine, including the alteration of body temperature, are presumably mediated by neuronal nicotinic acetylcholine receptors (nAChR). Previous studies have suggested the involvement of distinct nAChR subunits in nicotine-induced thermoregulation. We studied genetically manipulated knockout mice lacking the alpha7, alpha5 or beta4 subunit genes, in order to assess the effects of subunit deficiency on temperature regulation. Using a telemetry system, core body temperature was monitored continuously prior to and following nicotine administration in mutant mice and in wild-type littermates. Mice lacking in the beta4 nAChR subunit gene had significantly lower baseline core body temperature than all other mouse strains studied. beta4 null mice also demonstrated a reduced nicotine-induced hypothermic response and impaired desensitization following repeat nicotine exposure. These findings suggest the involvement of the beta4 nAChR subunit in both core body temperature homeostasis and nicotine-elicited thermo-alterations in mice.     

多巴胺D4受体基因与氯氮平临床疗效个体差异的关系

目的　探讨多巴胺D4受体基因第 3外显子 4 8bp可变重复序列多态性与氯氮平临床疗效个体差异的关系。方法　 81例精神分裂症患者单一服氯氮平治疗 6～ 8周 ,利用阳性与阴性症状量表 (PANSS)评定氯氮平的疗效。采用聚合酶链式反应 (PCR)、变性聚丙烯酰胺凝胶电泳结合银染技术 ,检测精神分裂症患者的基因型和等位基因频率。同时为排除氯氮平个体代谢能力的遗传差异带来的混淆 ,检测了每个患者的血清氯氮平浓度。结果　DRD4基因第 3外显子 4 8bp可变重复序列多态性的 5等位基因的纯合子基因型 (DRD4 5 / 5 )和 5等位基因 (DRD4 5 )的频率在氯氮平有效组和无效组之间有显著性差异。氯氮平治疗精神分裂症阳性症状、阴性症状的有效组和无效组间基因型及等位基因的频率相比无显著性差异。结论　氯氮平治疗精神分裂症的总疗效个体差异与DRD4基因第 3外显子 4 8bp可变重复序列相关 ,携带DRD4 5等位基因者和DRD4 5 / 5基因型者疗效好     

Association Study of Polymorphisms in Neuronal Nicotinic Acetylcholine Receptor Subunit Genes With Schizophrenia in the Han Chinese Population

ObjectiveTo investigate the relation between nicotinic acetylcholine receptor subunit (nAChR) genes and schizophrenia, and the relation between tag single nucleotide polymorphism (rs1317286, rs1044396, rs6494212, rs16969968, and rs684513) and schizophrenia in Han Chinese people. MethodsThe protein-protein interaction (PPI) network among nAChR protein and 350 proteins encoded by schizophrenia-related susceptibility genes was constructed through the String database to explore whether nAChR genes were associated with schizophrenia in these known databases. Then, five single nucleotide polymorphisms (SNPs) of CHRNA3 (rs1317286), CHRNA4 (rs1044396), CHRNA7 (rs6494212), and CHRNA5 (rs16969968, rs684513) were analyzed in a sample of 1,035 schizophrenic patients and 816 healthy controls. The interaction between the markers was analyzed using multifactor dimensionality reduction (MDR) software. Power analysis was performed using the Quanto program. ResultsThere are no significant differences in genotype or allele distribution were identified between the patients and controls (p>0.05). The haplotypes constructed by four markers rs1317286, rs6494212, rs16969968, and rs684513 were not associated with schizophrenia either. However, a significant association between models made of rs1317286, rs1044396, rs6494212, and rs684513 and schizophrenia was revealed in interaction analysis (p<0.05). ConclusionThe nAChR protein may have effects on the development of schizophrenia through the interaction with proteins encoded by schizophrenia-related susceptibility genes, but no relation was found between selected polymorphisms and schizophrenia in the collected Han Chinese people. However, interaction analysis suggested four-SNP model has an important effect on schizophrenia.