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研究生: 馮宜欣
I-Hsin Feng
論文名稱: TNF-α及IL-1α基因啟動子多型性與台灣帕金森氏症感受性的分子遺傳學研究
Molecular genetic study of TNF-α and IL-1α promoter polymorphisms in Parkinson's disease in Taiwan
指導教授: 李桂楨
Lee, Guey-Jen
學位類別: 碩士
Master
系所名稱: 生命科學系
Department of Life Science
論文出版年: 2006
畢業學年度: 94
語文別: 中文
論文頁數: 97
中文關鍵詞: 帕金森氏症腫瘤壞死因子間白素-1啟動子多型性
英文關鍵詞: Parkinson's disease, TNF-α, IL-1α, promoter SNP
論文種類: 學術論文
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  • 帕金森氏症(Parkinson's disease; PD)是常見的漸行性神經退化性症病之一,其臨床病症主要表現於運動失調上,患者中腦黑質的緻密區(substantia nigra pars compacta)會有多巴胺神經元死亡的現象,部分檢體的神經元突起處或是細胞核周圍會出現嗜伊紅性的細胞質內蛋白質包涵體,包含環境毒素、氧化壓力、細胞發炎反應、遺傳因素等都是可能造成PD發病的原因
    本研究主要在著重在tumor necrosis factor-α (TNF-α)啟動子T-1031C、C-863A、C-857T、G-308A及interleukin-1α (IL-1α)啟動子C-889T多型性與PD易感受性的相關研究。在遺傳層面上發現T-1031C、C-857T在PD病患與控制組間有顯著的差異(P = 0.0062及0.0035),但只有-1031CC基因型與PD的易感受性有關(Odds ratio: 2.96,95% CI: 1.38-7.09,P=0.0085)。利用SNPSpD分析發現-1031與-863有強力聯鎖情形(D'=0.93,Δ2=0.80),且-1031C/-863A的單套型也與PD的易感受性有關(Odds ratio=2.18,95% CI: 1.33-3.69,P=0.0028)。在基因功能性層面上的研究發現Raji細胞中-1031C會有較高的轉錄活性,-308A則有偏低的活性,使用ConA處理可誘發-1031C更高轉錄活性的表現,淋巴細胞株的研究則顯示帶有-1031CC/-863AA基因型其TNF-α mRNA表現量有些微增加的現象。
    IL-1α啟動子的研究上發現C-889T多型性在整體PD病患及控制組間並無顯著差異,但以發病年齡做區分可發現具-889 CT基因型的人其老年罹患PD的危險性會有顯著下降的情形(Odds ratio=0.31,95% CI: 0.13-0.71,P=0.0071),且TNF-α -1031T、-863C、-857C對偶基因對-889 CT基因型有顯著的加成效應。
    總結本研究發現無論在基因層面上TNF-α啟動子-1031CC的基因型具有較高罹患PD的危險性,且因強力聯鎖緣故,所以-1031C/-863A的單套型也具有較高罹患PD的危險性。功能性的研究也證實在Raji細胞系統中-1031C帶有較高的轉錄活性,ConA的處理則可增加-1031C高轉錄活性的效應。IL-1α -889 CT的基因型在大於70歲發病的PD族群中與控制組間有顯著的差異,顯示具有CT基因型的人老年時會有較低罹患PD的危險性,且TNF-α啟動子常見的多型性對偶基因對CT基因型有顯著的加成效果,其組合也會減少老年時罹患PD的危險性

    Parkinson’s disease (PD) is one of the most common neurodegenerative movement disorder. The hallmarks of PD are death of dopamine neurons in substantia nigra pars compacta and eosinophilic inclusions around the nucleus of neuron from PD patients. The etiology of PD is still not fully understood, but environmental toxicants, oxidative stress, inflammation, and gene dysfunction have thought to evoke PD.
    The focus of the study is to investigate the association of tumor necrosis factor-α (TNF-α) and interleukin-1α (IL-1α) promoter polymorphisms with the risk of PD. The overall genotype distribution at T-1031C and C-857T sites showed significant difference between PD cases and controls (P=0.0062 and 0.0035, respectively). However, only the more frequent -1031 CC genotype was evidently associated with PD (Odds ratio: 2.96, 95% CI: 1.38-7.09, P=0.0085). Using SNPSpD method showed that -1031 and -863 are in strong linkage disequilibrium (D'=0.93, Δ2=0.80). Pairwise Haplotype analysis among the four sites showed that -1031C-863A may act as a risk haplotype among PD cases (Odds ratio=2.18, 95% CI: 1.33-3.69, P=0.0028). Functional study revealed that -1031C allele drove greater transcriptional activity than common allele in Raji cell line. After stimulation with Concanavalin A (ConA), -1031C promoter activity was promoted to a significantly higher level than that of no stimulation. Using lymphoblastoid cells carrying -1031 CC/-863 AA genotype resulted in higher expression of TNF-α compared to cells carrying -1031 TT/-863 CC genotype.
    For IL-1α gene, the overall genotype distribution was not significantly different at C-889T site. However, when PD and control groups were stratified into >70 years subgroup the CT genotype frequency in PD was significantly less than controls (Odds ratio: 0.31, 95% CI: 0.13-0.71, P=0.0071). It suggested that people carrying -889 CT genotype reduced the probability of PD emergence, even aged. Multivariate analysis demonstrated the possible synergistic effect of the TNF-α promoter common alleles (-1031T, -863C, -857C) to IL-1α CT genotype in control group.
    In summary, the study demonstrated the association between the TNF-α -1301CC genotype, -1031C/-863A haplotype and susceptibility to PD. In Raji cell line, after stimulation with ConA -1031C allele drove significantly higher transcriptional activity than common allele, even before stimulation. In the onset age > 70 years subgroup, PD carrying IL-1α promoter CT genotype frequency was significantly less than controls, and the synergistic effect of the TNF-α promoter common alleles (-1031T, -863C, -857C) to IL-1α CT genotype in control group.

    目 錄 I 中文摘要 V 英文摘要 VII 圖 表 次 IX 壹、緒論 一、帕金森氏症(PD) 1 (一)臨床症狀 1 (二)神經病理學特徵 1 (三)病因學 3 1.環境因素 4 2.遺傳因素 7 二、發炎反應與PD的相關性 10 (一)發炎反應與神經退化性疾病 10 (二)TNF-α基因及其啟動子多型性 12 (三)IL-1α基因及其啟動子多型性 14 三、分子伴隨蛋白與PD的相關性 15 (一)分子伴隨蛋白與神經退化性疾病 15 (二)HSP-27基因 18 四、研究動機與目的 18 貳、研究材料與方法 一、研究樣品來源 20 二、細胞株的培養 20 三、基因組DNA的萃取 21 四、聚合酵素連鎖反應(PCR) 22 五、TNF-α、IL-1α、HSP-27基因多型性分析 22 (一)PCR-限制片段長度多型性分析(PCR-RFLP) 22 (二)統計分析 23 六、TNF-α啟動子片段的選殖 24 (一)多型性啟動子片段的製備 24 (二)接合反應(ligation) 24 (三)轉形勝任細胞(competent cell)之製備 24 (四)細菌的轉形作用(transformation) 25 (五)質體DNA的小量製備與DNA定序 25 (六)質體DNA的大量製備及純化 26 七、TNF-α多型性啟動子重組質體的構築 28 (一)pGL3 luciferase 報導基因系統的修改 28 (二)pGL3-TK/TNF-α多型性啟動子重組質體的構築與確認 28 八、TNF-α多型性啟動子重組質體的轉錄活性分析 29 (一)多型性啟動子重組質體的轉移(transfection)及誘導處理 29 (二)轉移之重組質體的轉錄活性測定與統計 30 九、TNF-α mRNA表現量檢測 31 (一)淋巴細胞株的誘導處理及RNA萃取 31 (二)Reverse transcription PCR (RT-PCR) 32 (三)同步定量PCR (Real-time PCR) 33 參、結果 一、TNF-α基因 35 (一)啟動子的多型性分析 35 (二)多型性的pairwise聯鎖不平衡檢測及單套型分析 35 (三)多型性啟動子在不同細胞株中的轉錄活性分析 36 (四)偶發性PD病患其內生性TNF-α mRNA之表現量 37 (五)淋巴細胞株經誘導後TNF-α mRNA的表現情形 38 1. LPS誘導處理 38 2. ConA誘導處理 39 二、IL-1α基因 40 (一)啟動子的多型性分析 40 (二)與TNF-α啟動子多型性的配對分析 41 三、HSP-27基因 42 肆、討論 一、TNF-α啟動子多型性影響個體對PD的感受性 43 二、TNF-α啟動子多型性對TNF-α轉錄活性的影響會因細胞而異 44 三、TNF-α啟動子多型性對TNF-α轉錄活性的影響會因基因的 聯鎖群而異 46 四、刺激物誘導TNF-α的表現會因細胞、劑量及處理時間而 有所差異 47 五、IL-1α啟動子多型性影響年長個體對PD的感受性 51 伍、參考文獻 55 陸、附錄圖表 71 圖一、神經發炎在PD神經細胞死亡的進程中所扮演的角色 71 圖二、pGL3-TK重組質體輿圖 72 圖三、pGL3-TK/TNF-α重組質體的構築 73 圖四、pGL3-TK/TNF-α重組質體的確認 74 圖五、TNF-α啟動子基因多型性檢測之洋菜膠體電泳照片 75 圖六、不同細胞株中TNF-α多型性啟動子的轉錄活性分析結果 76 圖七、Raji細胞經ConA誘導後TNF-α多型性啟動子的轉錄活性 分析結果 77 圖八、Real-time PCR分析偶發性PD患者內生性TNF-α mRNA的 表現量 78 圖九、不同濃度的LPS對淋巴細胞株TNF-α mRNA表現量的影響 79 圖十、各淋巴細胞株經LPS誘導後TNF-α mRNA表現量的差異 80 圖十一、不同濃度的ConA對淋巴細胞株TNF-α mRNA表現量的影響 81 圖十二、淋巴細胞株經ConA處理不同時間後其TNF-α mRNA的表現 82 圖十三、各淋巴細胞株經ConA誘導後TNF-α mRNA表現量的差異 83 圖十四、IL-1α啟動子基因多型性檢測之洋菜膠體電泳照片 84 圖十五、HSP-27基因多型性檢測之洋菜膠體電泳照片 85 表一、增幅TNF-α多型性片段、選殖啟動子片段、RT-PCR及 Real-time PCR的引子對及反應條件 86 表二、增幅IL-1α多型性片段的引子對及反應條件 88 表三、增幅HSP-27多型性片段的引子對及反應條件 89 表四、淋巴細胞株個別資料 90 表五、PD患者族群和控制組TNF-α啟動子多型性的分佈及其相關性 91 表六、TNF-α啟動子多型性的pairwise聯鎖不平衡檢測 92 表七、PD患者族群和控制組TNF-α啟動子的多型性單套型分析結果 93 表八、PD患者族群和控制組IL-1α啟動子多型性的分佈及其相關性 94 表九、大於70歲發病的PD患者族群和控制組其IL-1α及TNF-α 啟動子多型性的配對分析 95 表十、大於70歲發病的PD患者族群和控制組其IL-1α及TNF-α 啟動子多型性的多變量分析(multivariate analysis) 97

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