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研究生： 蔡維東
Tsai, Wei-Dung
論文名稱： 丙型干擾素、第一型干擾素調控因子及白三烯C4合成酶之基因多型性於氣喘病童中所扮演的角色
The Study of Genetic Polymorphisms of IFN-gamma, IRF1 and LTC4 Synthase in Asthmatic Children
指導教授： 呂政展
Lu, Cheng-Chan
王志堯
Wang, Jiu-Yao
學位類別： 碩士
Master
系所名稱： 醫學院 - 分子醫學研究所
Institute of Molecular Medicine
論文出版年： 2003
畢業學年度： 91
語文別： 中文
論文頁數： 188
中文關鍵詞： 基因多型性 、白三烯C4合成酶啟動子 、過敏性氣喘 、微小衛星重複序列多型性 、丙型干擾素 、遺傳關聯性研究 、單一核苷酸多型性 、干擾素第一型調控因子
外文關鍵詞： Interferon regulatory factor-1(IRF-1), Genetic association study, Leukotriene C4 synthase promoter (LTC4S promoter, Interferon-gamma(IFN-gamma), Atopic asthma, Microsatellite repeat polymorphism, Genetic polymorphism, Single nucleotide polymorphism(SNP)
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    • 　　氣喘，為一種氣道慢性發炎疾病，亦是在臺灣地區兒童中，最常見的肺部慢性疾病。 氣喘的主要症狀為支氣管過度反應及氣道反覆性的阻塞，進而導致呼吸不順、胸悶以及間斷性之哮喘。 在臺灣地區，小兒氣喘發生之主因，大都是由於吸入如塵蟎、花粉等過敏原，而引發免疫球蛋白E所誘發之過敏反應。 若依照氣喘病患氣管內細胞激素分泌之型式來加以區分，氣喘則是一種免疫系統之第二型輔助T細胞 (TH 2 cells) 過度表現之疾病。 丙型干擾素是一種為人所熟知，效力強大之免疫調控因子；同時，丙型干擾素在CD4+ T細胞分化成第一、第二型輔助T細胞的過程中，亦扮演了至為重要之角色。 已有一些基因鏈鎖關聯性研究已證實第十二號染色體長臂14 (12q14.1)以及第五號染色體長臂31 (5q31.1)之位置與過敏性氣喘有關聯性存在；而這兩個位置又恰巧分別是丙型干擾素基因 (IFNG)以及干擾素第一型調控因子基因 (IRF1)二者所在之位置。 丙型干擾素基因上相對於轉錄起始點之+999位置，有一T→A之單一核苷酸變異；已有文獻指出，此變異與體外細胞培養高度表現丙型干擾素有關。 此外，在日本兒童之研究樣本中，亦發現丙型干擾素基因上之CA重複序列及干擾素第一型調控因子基因上之GT重複序列多型性與過敏性氣喘有高度之關聯性。 在印度族群中，研究者則是觀察到丙型干擾素基因上之CA重複序列多型性與血清免疫球蛋白E表現之總量有密切之關聯性存在。 在先前之研究結果中，我們亦觀察到氣喘病童體內丙型干擾素之表現量，明顯地比對照組之丙型干擾素表現量為低，而此丙型干擾素表現量差異亦具有統計上之意義。 於本研究中，我們篩檢臺灣兒童族群中，丙型干擾素基因上可觀察到之多型性位置（這其中包括有–2653、+999、+2110和 +2322這四個單一核苷酸多型性位置以及一個微小衛星CA重複序列）及干擾素第一型調控因子基因上之GT重複序列多型性位置；並且比較氣喘、體內和體外細胞培養丙型干擾素表現量以及血清免疫球蛋白E總量，與上述這些多型性位置間，是否有關聯性存在。 同時於本研究中，以SSCP之方法發現一未曾被報導過之單一核苷酸多型性位置，其位在丙型干擾素基因轉錄子區段上游 –2653之位置，為T→G之單一核苷酸變異；此位置並經過直接定序分析加以證實。 由我們目前之研究結果顯示，於本研究中所篩選之多型性位置中，僅有丙型干擾素基因 +2110 A→G單一核苷酸變異與氣喘有密切之關聯性存在 (p = 0.011)。 +2110 A→G單一核苷酸變異亦與中度氣喘 (p = 0.012)及重度氣喘 (p = 0.023)有高度之關聯性，而非輕度氣喘。由丙型干擾素基因上兩兩單一核苷酸變異位置之組合，所進行之遺傳鏈鎖交互作用分析之結果，亦發現這些位置間的交互作用並不會增加氣喘發生的危險機率。 再者，經由K-W檢定亦得知，本研究所篩選之多型性位置，均與體內或是體外細胞培養丙型干擾素表現量，及血清免疫球蛋白E總量無關聯性存在。

    　　而另一方面，我們先前之研究結果亦揭櫫了，在氣喘舒緩期及急性期，氣喘病人尿液中白三烯E4 (LTE4)與前列腺素F2-alpha(PGF2-alpha)表現量，兩者之間有高度之相關性存在。 而本篇論文欲瞭解白三烯C4合成酶基因啟動子 (LTC4 synthase promoter)–444 A→C單一核苷酸變異與在氣喘舒緩期及急性期時，尿液中白三烯E4以及前列腺素F2-alpha表現量，是否有關聯性存在。 同時我們也比較了白三烯C4合成酶基因啟動子–444單一核苷酸變異之頻率分佈在過敏性氣喘和對照組之間是否有所差異。 實驗結果指出白三烯C4合成酶基因啟動子 –444單一核苷酸多型性與在氣喘舒緩期時，尿液中白三烯E4之表現量，有很強的關聯性存在 (p=0.026) ；此外，缺乏白三烯C4合成酶基因啟動子–444 C allele之氣喘病童，其在氣喘舒緩期尿液中白三烯E4表現量，會較帶有–444 C allele之氣喘病童，高出甚多。 但本研究之結果亦顯示，白三烯C4合成酶基因啟動子–444單一核苷酸多型性與過敏性氣喘，此二者並無關聯性存在。

    　　Asthma, a chronic airway inflammatory disorder, is the most common chronic lung disease of childhood in Taiwan. The characteristic symptoms of asthma are bronchial hyperresponsiveness, and reversible obstruction of the airways. Most asthma in children and teenagers is initiated by IgE-mediated hypersensitivity, resulting from inhaled allergens such as house dust mites, molds, or pollen grains. Based on the cytokine secretion patterns in the airway of asthmatics, it has been indicated that the CD4+ T cells are of the TH 2 cells. Interferon (IFN)-gamma is a well-known potent immunomodulator, which plays an important role in the differentiation of TH 1 and TH 2 cytokines. Genome-wide linkage analysis has demonstrated that 12q14.1 (IFNG), and 5q31.1 (IRF1) were associated with atopic asthma. T to A transversion at +999 IFNG single nucleotide polymorphism (SNP) has been shown to correlate with in vitro high IFN-gammaproduction. Besides, IFN-gamma gene CA-repeat and IRF-1 gene GT- repeat polymorphisms have been observed to significantly associate with atopic asthma in the Japanese child population. The CA- repeat polymorphism within IFN-gamma gene was signifi-cantly associated with total serum IgE (TsIgE) levels in the Indian population. Previously, we have shown that in vivo serum IFN-gamma levels of asthmatic children were statistically significantly lower than those of healthy controls. In this study, we purposed to investigate association of genetic polymorphisms (SNPs: –2653 T/G, +999 T/A, +2110 A/G and +2322 T/C; microsatellite: CA repeat) in the IFN-gamma gene and GT-repeat polymorphism in the IRF-1 gene with atopic asthma, in vivo and in vitro IFN-gamma production, and TsIgE levels in the Taiwanese child population. A novel SNP (T→G) was found at the upstream (–2653) of IFN-gamma promoter region by SSCP and was confirmed by sequence analysis. Recently, we revealed that only the distribution of IFN-gammagene+2110 A/G polymorphism significantly differs between asthmatics and healthy controls (p=0.011) in those of investigated IFN-gamma gene SNPs, CA-repeat microsatellite and IRF-1 gene GT-repeat microsatellite in our study; the distribution of +2110 A/G polymorphism was also associated with moderate asthma (p=0.012) and severe asthma (p=0.023), but not mild asthma. Two-by-two interactions between those of 4 SNP sites of IFN-gamma gene could not increase the risk of asthma. Furthermore, the distribution of all of screened SNPs and the CA- repeat within IFN-gamma gene and IRF1 GT-repeat failed to associate with in vivo and in vitro IFN-gamma production and TsIgE levels through Kruskal-Wallis test.

    　　In the other hand, preliminary data have shown that urinary LTE4 and PGF2-alpha levels were highly correlated in both acute and convalescent phase of asthma. In this report, we inspected the association of LTC4 synthase (LTC4S) promoter SNP, –444 A/C with urinary LTE4 and PGF2-alpha levels in acute and convalescent phase of asthma. We also investigated the distribution of LTC4S–444 SNP between atopic asthmatics and healthy controls. The result indicat- ed that there was a significantly association between LTC4S –444 A/C poly- morphism and urinary LTE4 levels in the convalescent phase of asthma (p=0.026). Besides, urinary LTE4 levels in the convalescent phase of asthma were significantly higher in asthmatics without –444 C allele than in asthmatics with -444 C allele. But there was no association between LTC4S –444 SNP and atopic asthma(p=0.026).

    [主 目 錄] 中文摘要…………………………………………………………………………Ⅰ 英文摘要…………………………………………………………………………Ⅳ 誌謝………………………………………………………………………………Ⅵ 主目錄……………………………………………………………………………Ⅶ 表目錄……………………………………………………………………………ⅩⅤ 圖目錄……………………………………………………………………………ⅩⅨ 第一章、導論……………………………………………………………………1 　第一節、漫談氣喘……………………………………………………………1 　　1.1-1 何謂氣喘…………………………………………………………… 1 　　1.1-2 氣喘之流行病學…………………………………………………… 1 　　1.1-3 氣喘之病理特徵與臨床表現……………………………………… 2 　　1.1-4 致使氣喘發生之免疫致病機轉…………………………………… 3 　　1.1-5 與氣喘相關之遺傳研究…………………………………………… 5 　第二節、丙型干擾素與氣喘之關聯性……………………………………… 7 　　1.2-1 丙型干擾素………………………………………………………… 7 　　1.2-2 丙型干擾素之基本特性…………………………………………… 9 　　1.2-3 丙型干擾素所誘發之訊號傳遞反應……………………………… 9 　　1.2-4 丙型干擾素於免疫系統中所扮演之角色………………………… 10 　　1.2-5 丙型干擾素與氣喘之關聯………………………………………… 11 　　1.2-6 丙型干擾素基因之多型性研究…………………………………… 12 　第三節、干擾素第一型調控因子與氣喘之關聯性………………………… 14 　　1.3-1 干擾素第一型調控因子…………………………………………… 14 　　1.3-2 干擾素第一型調控因子基因多型性及其與氣喘之關聯性研究…16 　第四節、白三烯C4合成酶基因多型性與氣喘、白三烯E4表現量以 　　　　　及前列腺素F2-alpha表現量之關聯性 ………………………… 17 　　1.4-1 白三烯C4合成酶基因-444 A/C單一核苷酸多型性 ………………17 　　1.4-2 白三烯C4合成酶基因-444 A/C單一核苷酸變異與氣喘之關聯性…18 　　1.4-3 白三烯C4合成酶基因-444 A/C單一核苷酸變異與白三烯E4 　　　　　表現量以及前列腺素F2-alpha表現量之關聯性研究……………19 第二章、材料與方法……………………………………………………………21 　第一節、研究樣本之來源及氣喘之評估標準………………………………21 　　◆實驗組……………………………………………………………………21 　　◆控制組…………………………………………………………………… 21 　　◆氣喘臨床診斷之標準…………………………………………………… 21 　第二節、萃取去氧核醣核酸之方式………………………………………… 23 　　◆傳統萃取方式…………………………………………………………… 23 　　　￠實驗材料及試劑之配製……………………………………………… 23 　　　￠實驗步驟……………………………………………………………… 24 　　◆以Blood and Tissue Genomic DNA Miniprep System萃取DNA ………… 27 　　　￠實驗材料及試劑之配製……………………………………………… 27 　　　￠實驗步驟……………………………………………………………… 28 　第三節、血漿中及細胞培養上清液中丙型干擾素含量之量測…………… 30 　　◆實驗原理………………………………………………………………… 30 　　　￠實驗材料及試劑之製備……………………………………………… 30 　　　￠實驗步驟……………………………………………………………… 33 　第四節、人體外體細胞培養及刺激周邊血液單核球增生之方式………… 34 　　◆實驗原理………………………………………………………………… 34 　　　￠實驗材料及試劑之配製……………………………………………… 35 　　　￠實驗步驟 ……………………………………………………………… 36 　第五節、於族群樣本中丙型干擾素基因單一核苷酸變異之篩檢………… 38 　　◆實驗原理………………………………………………………………… 38 　　◆丙型干擾素基因上單一核苷酸多型性位置之篩檢…………………… 39 　　　￠Direct Sequencing……………………………………………………… 39 　　　　Ⅰ.QIAquick Gel Extraction Kit……………………………………… 39 　　　　Ⅱ.PCR-MTM Clean Up System……………………………………… 41 　　　￠SSCP (Single-Strand Conformational Polymorphism) ……………… 42 　　　　Ⅰ.實驗材料及試劑之配製…………………………………………… 43 　　　　Ⅱ.實驗步驟…………………………………………………………… 44 　　　￠以Auto-Sequencer (ABI PRISMTM 377)定序………………………… 45 　第六節、利用PCR-SSP測定丙型干擾素基因之單一核苷酸變異基因型… 46 　　◆實驗原理………………………………………………………………… 46 　　◆丙型干擾素基因啟動子區域–2653位置單一核苷酸變異之測定…… 47 　　◆丙型干擾素基因第一插入子+999位置單一核苷酸變異之測定……… 48 　　◆丙型干擾素基因第三插入子+2322位置單一核苷酸變異之測定…… 50 　　◆實驗步驟…………………………………………………………………52 　第七節、利用PCR-SSOP測定丙型干擾素基因第三插入子+2110位置 　　　　　之單一核苷酸變異基因型………………………………………… 53 　　◆實驗原理………………………………………………………………… 53 　　◆丙型干擾素基因第三插入子+2110位置單一核苷酸變異之測定…… 54 　　　￠實驗材料及試劑之製備……………………………………………… 55 　　◆實驗步驟………………………………………………………………… 57 　第八節、利用GeneScan估算丙型干擾素基因及第一型干擾素調控因 　　　　　子上之微小衛星重複序列片段長度……………………………… 58 　　◆實驗原理………………………………………………………………… 58 　　◆丙型干擾素基因CA微小衛星重複序列多型性及第一型干擾素調控 　　　因子之GT微小衛星重複序列多型性之測定…………………………… 59 　　　Ⅰ.丙型干擾素基因之微衛星重複序列多型性部份…………………… 59 　　　Ⅱ.第一型干擾素調控因子基因之重複序列多型性部份……………… 61 　　◆實驗步驟及結果之判讀………………………………………………… 62 　第九節、利用PCR-RFLP測定白三烯C4合成酶基因啟動子之單一核苷 　　　　　酸變異基因型……………………………………………………… 64 　　◆實驗原理………………………………………………………………… 64 　　◆白三烯C4合成酶基因啟動子-444位置單一核苷酸變異之測定……… 66 　　◆實驗步驟………………………………………………………………… 67 　第十節、統計分析方法……………………………………………………… 68 　　◆比較實驗組及控制組間之基因多型性分佈頻率是否有所差異……… 68 　　◆比較實驗組及控制組間血清丙型干擾素含量之差異………………… 69 第三章、結果…………………………………………………………………… 72 　第一節、氣喘病童與非氣喘學童樣本之基本特性………………………… 72 　第二節、丙型干擾素於氣喘病童及非氣喘學童間表現量之差異………… 72 　第三節、丙型干擾素於不同嚴重度之氣喘病童間表現量之差異………… 74 　第四節、丙型干擾素基因單一核苷酸多型性位置於臺灣族群之分佈…… 75 　第五節、丙型干擾素基因單一核苷酸多型性與氣喘之關聯性…………… 76 　第六節、丙型干擾素基因單一核苷酸多型性位置間之鏈鎖不平衡……… 79 　第七節、丙型干擾素基因單一核苷酸多型性間之交互作用以及其與氣 　　　　　喘之關聯性………………………………………………………… 80 　第八節、丙型干擾素基因單一核苷酸多型性與丙型干擾素表現量間之 　　　　　關聯性……………………………………………………………… 82 　第九節、丙型干擾素基因CA重複序列多型性與氣喘之關聯性…………… 83 　第十節、丙型干擾素基因CA重複序列多型性與丙型干擾素表現量間之 　　　　　關聯性……………………………………………………………… 85 　第十一節、干擾素第一調控因子基因GT重複序列多型性與氣喘之關聯性.86 　第十二節、干擾素第一型調控因子基因GT重複序列多型性與丙型干擾 　　　　　　素表現量間之關聯性…………………………………………… 87 　第十三節、丙型干擾素基因多型性、干擾素第一調控因子基因GT重複 　　　　　　序列多型性與免疫球蛋白E之關聯性…………………………… 90 　第十四節、白三烯C4合成酶基因啟動子-444位置A/C單一核苷酸多型性 　　　　　　與氣喘間之關聯性……………………………………………… 93 　第十五節、白三烯C4合成酶基因啟動子-444位置A/C單一核苷酸多型性 　　　　　　與白三烯E4表現量間之關聯性………………………………… 94 　第十六節、白三烯C4合成酶基因啟動子-444位置A/C單一核苷酸多型性 　　　　　　與前列腺素F2-alpha表現量間之關聯性……………………… 96 　第十七節、白三烯C4合成酶基因啟動子-444位置A/C單一核苷酸多型性 　　　　　　與血清免疫球蛋白總量間之關聯性…………………………… 98 第四章、討論…………………………………………………………………… 162 　第一節、丙型干擾素基因多型性之研究…………………………………… 162 　第二節、基因單一核苷酸多型性暨重複短序列多型性之判定…………… 163 　　4.2-1 丙型干擾素基因單一核苷酸多型性……………………………… 163 　　4.2-2 微衛星重複短序列多型性………………………………………… 164 　　4.2-3 白三烯C4合成酶基因-444位置單一核苷酸多型性……………… 164 　第三節、丙型干擾素基因單一核苷酸多型性與氣喘發生暨丙型干擾素 　　　　　表現間之關聯性…………………………………………………… 165 　第四節、丙型干擾素基因CA重複序列、丙型干擾素調控因子GT重複序 　　　　　列與氣喘暨丙型干擾素表現量間之關聯………………………… 166 　第五節、丙型干擾素表現與氣喘發生間之關聯性………………………… 168 　第六節、丙型干擾素基因單一核苷酸多型性間之交互作用……………… 168 　第七節、丙型干擾素基因多型性、干擾素第一調控因子基因GT重複序 　　　　　列與血清免疫球蛋白E總量之關係 ……………………………… 169 　第八節、白三烯C4合成酶基因-444 A/C多型性位置與氣喘之關聯性…… 170 　第九節、總結………………………………………………………………… 170 附錄……………………………………………………………………………… 173 參考文獻………………………………………………………………………… 176 [表 目 錄] 表一： Basic characteristics of asthmatics and controls in our subjects …………………………………………………………………………………… 99 表二： Comparison of total serum IgE and IFN-gamma levels between asth- tics and controls …………………………………………………………… 100 表三： The relationship of IFN-gamma levels to asthmatic status ………… 101 表四之一： Primers used in the SSCP screening of IFN-gamma gene ………… 102 表四之二： Single nucleotide polymorphisms in the human IFN-gamma Gene in Taiwanese population …………………………………………………… 104 表四之三： Recently identified polymorphisms in the human IFNG gene ……………………………………………………………………………… 105 表五： Distributions of IFNG genotype and allele frequencies between asthmatics and controls …………………………………………………… 107 表六： Distribution of IFNG genotype frequencies between various asth- matic status and controls ………………………………………………… 108 表七： Distribution of IFNG allele frequency between various asthmatic status and controls ………………………………………………………… 109 表八之一： Linkage analysis among IFN-gamma gene polymorphic sites in total sample population ……………………………………………… 110 表八之二： Linkage analysis among IFN-gamma gene polymorphic sites in asthmatics ………………………………………………………………… 111 表八之三： Linkage analysis among IFN-gamma gene polymorphic sites in controls …………………………………………………………………… 112 表九：Two-by-two tests of pairs of IFN-gamma geneSNPs in atopic asthma…113 表10.a： Association between IFN- gene SNPs and in vivo IFN-gamma levels in total population ………………………………………………………… 118 表10.b： Association between IFN-gamma gene SNPs and in vivo IFN-gamma levels ………………………………………………………………………… 119 表11.a： Association between IFN-gamma gene SNPs and total serum IgE levels in total population ……………………………………………… 120 表11.b： Association between IFN-gamma gene SNPs and total serum IgE levels …………………………………………………………………………………… 121 表十二： Association between IFN-gamma gene SNPs and in vitro PHA-stimulated IFN-gamma levels …………………………………………………………… 122 表十三： Proportion of expressing 1st intron CA repeat in the IFN-gamma gene in our subjects ……………………………………………………………… 123 表十四： Allele frequencies of IFNG gene CA repeat polymorphism in patients with atopic asthma and controls ………………………………………… 124 表十五： Proportion of expressing IFNG gene CA repeat between each kind of asthmatic status and controls …………………………………………… 125 表16.a： Association between expressing IFNG gene CA repeat polymorphisms and in vivo IFN-gamma levels in total population ………………… 126 表16.b： Association between expressing IFNG gene CA repeat polymorphisms and in vivo IFN-gamma levels …………………………………………… 127 表17.a： Association between expressing IFNG gene CA repeat polymorphisms and total serum IgE levels in total population …………………… 128 表17.b： Association between expressing IFNG gene CA repeat polymorphisms and total serum IgE levels ……………………………………………… 129 表十八： Association between expressing IFNG gene CA repeats and in vitro PHA-stimulated IFN-gamma levels ………………………………………… 130 表十九： Distribution of in vitro PHA-stimulated IFN-gamma levels among various IFNG CA-repeat allele patterns ……………………………… 131 表二十： Proportion of expressing 7th intron GT repeat in the IRF-1 gene in our subjects ……………………………………………………………… 132 表二十一： Allele frequencies of IRF1 gene GT repeat polymorphism in patients with atopic asthma and controls ………………………… 133 表二十二： Proportion of expressing IRF1 gene GT repeat between each kind of asthmatic status and controls ……………………………… 134 表23.a： Association between expressing IRF1 gene GT repeat polymorphisms and in vivo IFN- levels in total population ……………………… 135 表23.b： Association between expressing IRF1 gene GT repeat polymorphisms and in vivo IFN-gamma levels …………………………………………… 136 表24.a： Association between expressing IRF1 gene GT repeat polymorphisms and total serum IgE levels in total population …………………… 137 表24.b： Association between expressing IRF1 gene GT repeat polymorphisms and total serum IgE levels ……………………………………………… 138 表二十五： Association between expressing IRF1 gene GT repeats and in vitro PHA-stimulated IFN-gamma levels …………………………… 139 表二十六： Distribution of in vitro PHA-stimulated IFN-gamma levels among various IRF1 GT-repeat allele patterns …………………………… 140 表二十七： Differences in in vitro PHA-stimulated IFN-gamma levels between IRF1 GT-repeat allele 2 patterns …………………………………… 141 表二十八： Association of LTC4 synthase gene promoter -444 polymorphism with Asthma ……………………………………………………………… 142 表二十九： LTC4 synthase promoter region -444 allele frequency in asth- matics compared with controls ……………………………………… 143 表三十： Association between leukotriene_C4 synthase promoter –444 poly- morphism and LTE4-Pre levels in asthmatics' urine …... 144 表三十一： Association between leukotriene_C4 synthase promoter -444 polymorphism and LTE4-Post levels in asthmatics' urine ……… 145 表三十二： Association between LTC4 synthase promoter –444 polymorphism and PGF2-alpha-Pre levels in asthmatics' urine ………………… 146 表三十三： Association between LTC4 synthase promoter –444 polymorphism and PGF2-alpha-Post levels in asthmatics' urine ……………… 147 表三十四： Association between LTC4S promoter –444 C allele non-expre- ssion and LTE4-Post Levels in Asthmatics' urine ……………… 148 表三十五： Association between LTC4S promoter –444 C allele expression and TsIgE levels in general population ………………………… 149 附錄一： Summary of Genome-Wide Linkage Studies for Atopic Phenotypes within the Past Few Years ……………………………………………… 173 附錄二： Primers Used in the Analysis of IFN-gamma Gene ………………… 174 [圖 目 錄] 圖一： Localization of polymorphic sites in the human IFN-gamma gene … 150 圖二： Detected novel –2653 T/G polymorphism localized at IFN-gamma promoter by SSCP and was confirmed by direct sequencing ………… 151 圖三： Detected +2110 A/G polymorphism localized at IFN-gamma 3rd intron by SSCP and was confirmed by direct sequencing ……………………… 152 圖四： Using PCR-based SSP to determine IFN-gamma promoter –2653 T/G polymorphism …………………………………………………………………… 153 圖五： Using PCR-based SSP to determine IFN-gamma promoter +999 T/A poly morphism ………………………………………………………………………… 153 圖六： Using PCR-based SSP to determine IFN-gamma gene +2322 T/C poly- morphism ………………………………………………………………………… 154 圖七： Genotyping of IFN-gamma gene +2110 G/A polymorphism by SSOP analysis ……………………………………………………………………………………… 155 圖八： Microsatellite length predictions of IFN-gamma gene 1st intron CA repeat and IRF-1 gene 7th intron GT repeat by GeneScan analysis … ……………………………………………………………………………………… 156 圖九： Using PCR-RFLP to detect LTC4 synthase promoter -444 A/C polymor- phism ……………………………………………………………………………… 157 圖十： Different LTE4-pre Levels between LTC4S -444 A/A and A/C in Acute Phase of Childhood Asthmatics ……………………………………………… 158 圖十一： Different LTE4-post Levels between LTC4S -444 A/A and A/C in Con- valescent Phase of Childhood Asthmatics ……………………………… 158 圖十二： Different PGF2-alpha-pre Levels between LTC4S -444 A/A and A/C in Acute Phase of Childhood Asthmatics …………………………………… 159 圖十三： Different PGF2-alpha-post Levels between LTC4S -444 A/A and A/C in Convalescent Phase of Childhood Asthmatics ………………………… 159 圖十四： Different LTE4 Levels between Expression and Non-expression of LTC4S -444 C alleles in Convalescent Phase of Asthma …………… 160 圖十五： Different TsIgE Levels between Expression and Non-expression of LTC4S -444 C alleles in the Taiwanese Population ………………… 160 圖十六： Box-plot for the differences of in vitro PHA-stimulated IFN-gamma levels between various IFN-gamma gene CA-repeat allele 2 ……… 161 附錄三： The Formation of Leukotrienes by the 5-Lipoxygenase Pathway ………………………………………………………………………………… 175

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