台灣地區兒童氣喘的盛行率在過去40年已經增加九倍。由70年代的1.3%到近年來的10-14%。來自世界各地的研究顯示在不同族群的染色體內各有許多不同基因與氣喘病有相關。證據也顯示過敏敏感是可以在胎幼兒期就開始，並且可能因此延續到後來氣喘或過敏病的形成。流行病學研究發現氣喘盛行率在已開發國家比開發中國家高許多；而且城市區域的氣喘盛行率也比鄉村地區高。這些結果顯示文明發展後的環境因素可以啟動過敏基因，使得過敏病增加。因此，到底是甚麼免疫基因在胎幼兒至孩童期會隨著性別、年紀、和環境等的不同，對過敏病的形成或免除開啟關鍵的作用？我們為了解開此謎題，透過與高雄長庚紀念醫院婦產科、小兒科的合作，針對1,211個核心家庭的胎幼兒進行產前到產後追蹤的世代研究，探索可能和過敏有關的159個基因中384個關鍵性基因多型性。初步發現14個基因與臍帶血免疫球蛋白E產生的增加有關聯性；一歲半時有12個基因；三歲時有15個基因；六歲時則有12個基因與免疫球蛋白E產生的增加有關聯性。其中CX3CL1，IL13，PDGFRA，FGF1的基因多型性與新生兒、一歲半和三歲的免疫球蛋白E上昇有關，而HLA-DPA1，HLA-DQA1，CCR5，IL5RA和六歲的免疫球蛋白E上昇有關，顯示這個關聯性會隨著嬰幼兒在不同階段的發育（新生兒、一歲半、三歲、六歲）而有不同。利用資料簡化策略所發展出來的「多因子降維法」分析，在不同時期發現不同類型的基因間存在著交互作用，進而造成免疫球蛋白E的增加，例如：IL13基因的rs1800925、CYFIP2的rs767007和PDE2A的rs755933之間的基因－基因交互作用，與三歲大的免疫球蛋白E生產有顯著的相關性存在。顯然某些基因的不同基因型會隨著個體在發育過程中，對免疫球蛋白E的產生有著不同程度的影響。由於血液中免疫球蛋白E的濃度是評估過敏病和過敏體質的重要指標，我們相信透過同時追蹤基因和產前至孩童期的免疫球蛋白E增加，或可找到早期診斷過敏敏感和防治過敏病的方案。

Prevalence of childhood asthma in Taiwan has increased 9 times from 1.3% to 10-14% in the past 4 decades. Many studies worldwide have demonstrated that many genes in different chromosomes are implicated in childhood asthma in different ethnic populations. A growing body of evidence suggests that allergic sensitization could occur in perinatal stage and correlate to the development of childhood asthma. Epidemiological studies, however, indicate that prevalence of childhood asthma is much higher in developed countries than that in developing countries; and prevalence of childhood asthma in metropolitan area is higher than that in country sites. This suggests that certain genes can interact with the environmental factors in developed countries to promote the development of childhood atopic disorders. Interests are now increasing on what is (are) the real pathogenic gene-gene interaction(s) for childhood atopic disorders under influence of age, gender and environmental factors? In a large perinatal cohort study with 1,211 pregnant women and their offspring from the obstetrics and pediatrics of Kaohsiung Chang Gung Memorial Hospital, we analyzed 159 allergy candidate genes with 384 single nucleotide polymorphisms and showed that 14 genes over 22 somatic and X chromosomes risk to or protective from cord blood immunoglobulin E (CBIgE) elevation are different from those genes associated with IgE elevation in children under 1.5, 3 and 6 years of age (12, 15 and 12 genes, respectively). CX3CL1, IL13, PDGFRA and FGF1 polymorphisms were associated with elevated IgE at earlier ages (newborn, 1.5 and 3 years); HLA-DPA1, HLA-DQA1, CCR5 and IL5RA polymorphisms were associated with IgE production at 6 years of age. Further analysis by multifactor dimensionality reduction (MDR) developed from data reduction strategy, we found that there are interactions among innate immunity, adaptive immunity, and response and remodeling genes on IgE production begin in prenatal stage. For example, The gene-gene interaction among IL13, rs1800925, CYFIP2, rs767007 and PDE2A, rs755933 was significantly associated with IgE production at 3 years of age. This suggests that different genotypes of genes interact one another on the IgE production contributing to the development of allergic diseases. Since the concentration of IgE is an important indicator of atopic disorders and allergic sensitization, we believe after clarifying the natural course of the genomic profiles on IgE elevation, certain early predictor(s) and preventive regimens for allergic sensitization or atopic disorders may be made possible.

誌謝…………………………………………………………i
中文摘要……………………………………………………ii
英文摘要……………………………………………………iii
縮寫對照表…………………………………………………v
圖次…………………………………………………………vii
表次………………………………………………………viii
前言與研究目的……………………………………………1
材料與方法…………………………………………………5
實驗對象，血液收集和IgE的測量………………………5
DNA的萃取和父母親atopic diseases的定義……………5
訂製SNP的選擇和384 SNPs microarray的上機與分析..6
以限制酵素片段長度多型性(Restriction Fragment Length Polymorphism；RFLP)方法的平行實驗確認384 SNPs microarray結果的準確性…………………………6
資料分析和統計……………………………………………7
結果…………………………………………………………8
研究對象和demographic data………………………8
孩童時期IgE生產與SNP的相關性………………………8
以MDR分析在孩童時期IgE生產和基因－基因的交互作用……………………………………………………………9
討論………………………………………………………12
參考文獻…………………………………………………49

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