簡國龍臺灣大學:預防醫學研究所謝青宙Hiseh, Ching-JowChing-JowHiseh2010-06-022018-06-292010-06-022018-06-292009U0001-2107200916041600http://ntur.lib.ntu.edu.tw//handle/246246/184870背景與目標：遲發性運動異常 (Tardive dyskinesia, TD)，是抗精神病藥物副作用中較嚴重的一種。TD的病理機轉目前並未完全了解，有研究指出與血清素基因有關。本研究目的為探討血清素第2A型接受體T102C 基因多型性、血清素運送基因多型性與血清素第2C型接受體Cys23Ser基因多型性與慢性精神分裂症患者之TD有無相關。法：本研究屬於遺傳的相關性研究。評估於台灣具代表性的兩家精神科專科醫院之慢性住院精神分裂症病患，再以有無TD現象分為TD組 (n=32)與non-TD組 (n=135)，並有正常對照組 (n=91)參與，所有參加者皆為台灣漢族人。實驗室方面將抽血得到之白血球所抽出的DNA進行聚合鏈反應，以瞭解各基因多型性在TD組與non-TD組的分布是否有差異。並以logistic regression 調整相關變項，及根據年齡與性別做次族群的分析。果：於血清素第2A型接受體基因，TD組相較於non-TD組有較少的CC及CT基因型 (P=0.022)；C allele frequency於TD組為29.7%，於non-TD組為45.6%，兩組的allele分布亦已達統計上顯著差異 (P=0.021)。經logistic regression調整變項後，TD的有無僅與血清素第2A型接受體基因多型性有統計上的相關，特別是在顯性模式 (OR=0.26, 95%CI=0.10-0.71, P=0.008) 與加成性模式 (OR=0.40, 95% CI=0.19-0.86, P=0.019)。於血清素運送基因多型性與血清素第2C型接受體基因多型性則與TD沒有相關。於次族群分析，年齡大於等於50 歲 (OR=0.28, 95% CI=0.10-0.84, P=0.022) 及男性病患 (OR=0.033, 95% CI=0.003-0.37, P=0.006)，其血清素2A接受體基因多型性與TD相關。論：本研究發現血清素第2A型接受體T102C基因多型性，會影響台灣漢族慢性精神分裂症患者的TD發生。Background and Objective: Tardive dyskinesia (TD) is a serious side effect of antipsychotics. Although the pathogenesis of TD is still not fully understood, studiesave reported TD is associated with serotonin genes. This study is aimed at exploring the association between the serotonin gene polymorphisms (HTR2A T102C, 5-HTTLPR, HTR2C Cys23Ser) and chronic schizophrenic patients with or withoutD.ethods: Genetic association study with case control design was performed to analyze the allele and genotype frequencies of schizophrenia patients with TD (n=32),atients without TD (n=135), and normal control participants (n=91). All participants are Ethnic Han Taiwanese. Genotyping of HTR2A T102C polymorphism, 5-HTTLPRolymorphism and HTR2C Cys23Ser polymorphism were performed by polymerase chain reaction-based restriction analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed by multivariate logistic regression analysis. Subgroup analysis was performed according to age and gender.esults: The C allele frequency of HTR2A is 29.7% in TD group and 45.6% in non-TD group (P=0.021). Patients carrying C allele were likely to be protected fromD (OR=0.26, 95% CI=0.10-0.71, P=0.008 for dominant mode; OR=0.40, 95% CI=0.19-0.86, P=0.019 for additive mode). However, no association between 5-HTTLPR and HTR2C polymorphisms and TD was found. HTR2A T102C was associated with TD in subgroup of older than 50 years (OR=0.28, 95% CI=0.10-0.84, P=0.022) and men (OR=0.033, 95% CI=0.003-0.37, P=0.006).onclusion: Our findings support that HTR2A T102C polymorphism influences the susceptibility to antipsychotics-induced TD in the chronic schizophrenic patients in Taiwan.目錄試委員會審定書謝文摘要文摘要一章 研究背景....................................................................................1一節 抗精神病藥物的發展與作用機轉..........................................2.1.1 精神分裂症的多巴胺假說…………………………………..2.1.2 抗精神病藥物的療效機轉及其副作用……………………..3二節 錐體外路徑副作用的分類與評估..........................................5.2.1 分類與診斷準則……………………………………………..5.2.2 錐體外路徑副作用的評估工具……………………………..7.2.3 錐體外路徑副作用的病理機轉與基因相關性研究………..9三節 抗精神病藥物所引發之遲發性運動異常........................…10.3.1 遲發性運動異常的簡介……………………………………10.3.2 遲發性運動異常的盛行率與嚴重性………………………11四節 遲發性運動異常相關文獻之回顧…………………………12.4.1 遲發性運動異常的危險因子………………………………12.4.2 遲發性運動異常的病理機轉假說…………………………17I.4.3 遲發性運動異常的病理機轉與基因相關性研究………. …19二章 研究目的..................................................................................25三章 材料與方法..............................................................................26一節 研究設計................................................................................26二節 研究族群及收案標準……………………………………..26.2.1 研究族群…………………………………………………..26.2.2 收案標準…………………………………………………..27三節 研究進行方式……………………………………………..28.3.1 資料收集…………………………………………………..28.3.2 診斷與TD病例之標認………………………………… ..28.3.3 主要的研究變項…………………………………………..30.3.4 基因分析…………………………………………………..31四節 統計方法…………………………………………………..32五節 樣本數的估計……………………………………………..34四章 結果..........................................................................................35一節 描述性資料…………………………………………………35二節 Genottype and allllelle 的頻率與分布………………………..35.2.1 哈温平衡測試………………………………………………..35II.2.2 Genotype and allele的頻率與分布………………………….36三節 調整干擾因子……………………………………………....37.3.1 血清素2A接受體基因多型性………………………………37.3.2 血清素運送基因多型性……………………………………..38.3.3 血清素2C接受體基因多型性………………………………39四節 次族群分析………………………………………………..39.4.1 血清素2A接受體基因多型性………………………………39.4.2 血清素運送基因多型性……………………………………..40.4.3 血清素2C接受體基因多型性………………………………40五章 討論…………………………………………………………..41一節 描述性說明本研究主要結果……………………………....41二節 相較於過去的研究………………………………………..42三節 生物學的機轉……………………………………………..44四節 臨床意涵…………………………………………………..45五節 本研究之優勢……………………………………………..45六節 本研究之限制……………………………………………..46七節 未來研究方向……………………………………………..48八節 結論………………………………………………………..48IIIABLES....................................................................................................50 . Comparison of AIMS and ESRS ………………………………….50I. Comparison of DSM-IV and ICD-10……………………………..51II. Literature review of 5-HT polymorphisms and TD ……………...52V. Characteristics of serotonin SNPs ……………………………….54. Basic characteristics of schizophrenic patients with and without TD………………………………………………………………....55I. Results of the Hardy-Weinberg equilibrium test in the studyopulation………………………………………………………56II. Genotype and allele frequencies in schizophrenic patients with andithout TD……………………………………………………...57III. The coefficient, standard error of mean, significant level, anddds ratio for TD in the study participantsable VIII-1A. Co-dominant mode of HTR2A……………………...58able VIII-1B. Additive mode of HTR2A…………………………..59able VIII-1C. Dominant mode of HTR2A…………………………60able VIII-1D. Recessive mode of HTR2A…………………………61able VIII-2A. Co-dominant mode of 5-HTTLPR………………….62able VIII-2B. Additive mode of 5-HTTLPR………………………63able VIII-2C. Dominant mode of 5-HTTLPR……………………..64able VIII-2D. Recessive mode of 5-HTTLPR……………………..65able IX. The estimated parameters, odds ratios, 95%CIs of theolymorphism for the risk of TD after adjustment for agend gender, education years, marital status, job status,lcohol drinking, smoking, diabetesable IX-1. HTR2A …………………………………………………66able IX-2. 5-HTTLPR ……………………………………………...67able X. Logistic regression models for participants with and withoutDable X-1. HTR2A…………………………………………………...68able X-2. 5-HTTLPR……………………………………………….69Xable XI. The odds ratios, 95%CIs of the polymorphism for the risk ofD according to age group and genderable XI-1. HTR2A…………………………………………………..70able XI-2. 5-HTTLPR………………………………………………71IGURES..................................................................................................72igure 1. Mechanisms and possible interactions in TD 72igure 2. Flow diagram of patients enrollment in the study 73igure 3. Sample size estimation based on minor allele frequency andelative risk 74igure 4. Power estimation based on minor allele frequency andelative risk 75考文獻………………………………………………………………..76錄……………………………………………………………………..86application/pdf1375144 bytesapplication/pdfen-US遲發性運動異常精神分裂症血清素第2A 型接受體基因血清素運送基因血清素第2C型接受體基因多型性Tardive dyskinesiaSchizophreniaSerotonin 2A receptor geneSerotonin transporter geneSerotonin 2C receptor genePolymorphismthesishttp://ntur.lib.ntu.edu.tw/bitstream/246246/184870/1/ntu-98-P96846004-1.pdf