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博碩士論文 etd-0323109-115415 詳細資訊
Title page for etd-0323109-115415
論文名稱
Title
共同刺激因子作為遺傳標記預測葛瑞茲氏病之復發
Costimulatory molecules as genetic markers for relapse of Graves’ disease
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
91
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2009-02-14
繳交日期
Date of Submission
2009-03-23
關鍵字
Keywords
CD40、PDCD-1、ICOS、CTLA-4、CD28、共同刺激因子、葛瑞茲氏症、單一核苷酸多型性、單套體
CD40, PDCD-1, ICOS, CTLA-4, CD28, costimulatory factor, Graves' disease, haplotype, single nucleotide polymorphism
統計
Statistics
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The thesis/dissertation has been browsed 5695 times, has been downloaded 2 times.
中文摘要
葛瑞茲氏症為器官專一性自體免疫疾病(organ specific autoimmune disease)。隨著免疫學與基因體學之發展,葛瑞茲氏症之基因遺傳研究在近年來也有快速的進步。除了第二型主要組織相容性複合體( major histocompatibility complex class II, MHC class II)之外,T細胞的活化與調節尚需要多種共同刺激因子、多重步驟共同調節。本研究探討此群共同刺激因子之基因多型性對葛瑞茲氏症,發生與復發是否有關,及是否可利用此群基因多型性預測葛瑞茲氏症患者之復發。
本研究於高雄長庚醫院招募志願者:新陳代謝科門診招募262位葛瑞茲氏症患者(女性214名;男性48名);健康檢查中心招募200名健康對照組(女性103名;男性97 名)。葛瑞茲氏症患者根據停藥後復發時間分為三組:GroupⅠ為停藥後小於或等於九個月之內復發;GroupⅡ為停藥後復發時間介於十個月至三十六個月;GroupⅢ為停藥後大於三十六個月復發或持續緩解。志願者進行血液學檢查( T3、T4、free T4、TSH、TBII與AMA);理學檢查(goiter大小)及家族史詢問;萃取志願者之周邊血液白血球DNA,利用限制&#37238;片斷長度多樣性與TagMan&#174; genotype assay進行基因多型性鑑定。使用Haploview software執行相近基因多型性之連鎖不平衡分析。使用Hap-Clustring program執行單套體分析。使用卡方檢定、一般線性模式多重回歸模式及Kaplan-Meier plot執行各項變因及相關統計之分析。在本研究p <0.01認定為有統計學上意義。
本研究結果顯示:(1)共同刺激因子之基因多型性與葛瑞茲氏症之發生與復發有相關;(2)葛瑞茲氏症患者比健康對照組攜帶較多risk alleles;(3)比較葛瑞茲氏症其各次族群,其個體攜帶的risk allele個數較多者其停藥後較早復發;(4) risk allele數目與治療後之goiter大小、TBII皆為預測患者是否復發之獨立因子;(5)以odds ratio為基礎的危害評分(risk score)顯示出risk score越高,其停藥後復發時間越短。由此分析結果可知共同刺激因子群與葛瑞茲氏症確有相關,且可使用此群共同刺激分子多型性建立預測此病預後之指標,做為選擇藥物治療或破壞性治療之參考指標之一。
Abstract
Graves’ disease (GD), an organ specific autoimmune disease, requires two signals to activate the T cells. In addition to the specific binding of T cell receptor to the antigenic peptide-MHC complex, an antigen-independent costimulatory pathway reportedly require generate subsequent cytokines and cell surface molecules. This regulation of T-cell response is a highly-organized multiple step program. T cell costimulatory signals is found to regulate the magnitude and duration of various type of autoimmune diseases. This study is to test whether genetic polymorphism of these costimulatory genes is related with the disease susceptibility or progression. We anticipated that the candidate genetic makers are beneficial for importing GD management.
We recruited 262 GD patients from the Outpatient Department of Endocrine and 200 healthy controls from the Health Screening Center of Chang Gung Memorial Hospital in Kaohsiung.The GD patients were divided into three groups: recurred within 9 months (n=91), between 10-36 months (n=65), and more than 36 months (n=106). Clinical and laboratory attributes included: the genotypes of CTLA-4, CD28, ICOS, PD-1 and CD40; serum levels of T4, T3 and TSH; goiter size and TSH-receptor antibodies at the beginning and end of treatment. Genomic DNA was extracted from peripheral blood leucocytes by kit. The single nuclotide polymorphisms of the candidate genes were genotyped by polymerase chain reaction- restriction fragment length polymorphism and TaqMan&#174; SNP Genotyping Assays with specific primers. Linkage disequilibuium between pairs of polymorphism was estimated by Haploview software. Haplotype analyses were performed using the Hap-Clustering program. Variance and correlation of data was statistically analyzed by Chi-square, general liner model, multiple logistic regression analysis and Kaplan-Meier plot. A p value <0.01 was considered significant.
The results showed:(1) Genetic polymorphism within the costimulatory molecules affected the susceptibility and progression of GD; (2) GD patients carried more risk alleles than the controls; (3) Within the GD group, patients harboring more risk alleles wound relapse earlier after drug withdrawal; (4) Number of risk alleles, goiter size and TBII levels at end of treatment were independent predictors of disease relapse; (5) A risk score calculation based on odds ratio of risk alleles correlated with patients’ relapse time after drug withdrawal.
We concluded that patients’ genetic makers of costimulatory molecules may be helpful in choosing appropriate treatment for GD.
目次 Table of Contents
中文摘要. Ⅰ
英文摘要 Ⅲ
名詞對照表 Ⅴ
一、緒論 P1
1.1導言 P1
1.2葛瑞茲氏症致病機轉 P2
1.3葛瑞茲氏症的治療模式 P3
1.4葛瑞茲氏症危險因子之概論 P3
1.4.2環境因素 P4
1.4.3基因因素 P6
1.5共同刺激因子與免疫反應 P9
1.5.1 CD28 P10
1.5.2 Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). P11
1.5.3 Inducible costimulator (ICOS P12
1.5.4 Programmed cell death-1 (PDCD-1) P12
1.5.5 CD40 P13
1.6基因標誌 P14
二、材料與方法 P16
2.1健康志願者及葛瑞茲氏症患者募集 P16
2.2DNA萃取 P17
2.3檢測single nucleotide polymorphism P18
2.3.1限制脢片斷長度多樣性 P19
2.3.1.1 Polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP)步驟 P19
2.3.2 TaqMan&#174; SNP Genotyping Assays P20
2.4 統計分析 P22
三、結果 P23
3.1健康對照組與葛瑞茲氏症患者個數、性別與年齡分佈 P23
3.2疾病易感性與易復發有關的single nucleotide polymorphism P23
3.3 Risk allele與葛瑞茲氏症之疾病易感性、復發之關連 P25
3.4比較risk allele 與其他臨床指標預測葛瑞茲氏症復發之效用 P27
3.5以odds ratio為基礎的危害評分系統(risk score) P28
四、討論與結論 P29
五、參考文獻 P35
表目錄
表一 Primer 序列 P48
表二 PCR reagent 配製 P49
表三 PCR protocol P50
表四 SNP與對應使用的限制脢 P51
表五RFLP reagent配製方法及反應溫度 P52
表六TaqMan&#174; SNP Genotyping Assays Reagent P53
表七 SNP Genotyping Assays 步驟 P54
表八 CD28、CTLA-4、ICOS之SNP位置與MAF P55
表九 PDCD-1之SNP位置與MAF P56
表十CD40之SNP位置與MAF P57
表十一 Candidate SNP 及分析結果 P58
表十二 CD28、CTLA-4、ICOS之連鎖不平衡(linkage disequilibrium matrix)相關數據 P62
表十三 PDCD-1之連鎖不平衡(linkage disequilibrium matrix)相關數據 P64
表十四CD40之連鎖不平衡(linkage disequilibrium matrix) 相關數據 P65
表十五Haplotype之組成 P66
表十六Risk allele 個數 在對照組與疾病組之分佈 P67
表十七 Risk allele 個數 在健康對照組與疾病組各次分組之分佈 P68
表十八Multiple logistic regression analysis for determinants of treatment outcome P69
表十九Polymorphisms associated with susceptibility and progression of GD P70
圖目錄
圖一共同刺激因子與免疫反應之活化 P73
圖二PCR-RFLP 電泳及結果判定 P74
圖三 TaqMan&#174; SNP Genotyping Assaysm原理 P75
圖四 CD28、CTLA-4、ICOS之SNP 位置與LD P76
圖五PDCD-1(左)、CD40(右)之SNP 位置與LD P77
圖六 Risk allele number level與Graves’ disease 復發之關係 P78
圖六 Risk score與Graves’ disease 復發之關係 P79
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