氣喘是一由多因子共同作用參與的疾病，這些因子主要可分成遺傳因子與環境污染因子兩大類。環境因子方面，最常被討論的是室內過敏原暴露，過敏原常見的有塵�@、蟑螂、貓毛與狗毛；在遺傳因子方面，b2-adrenergic receptor (b2AR；用來治療氣喘的b-agonist之受器), HLA-DR/-DQ，腫瘤壞死因子（TNF）等的基因多型性，都被認為是與氣喘有關的危險因子。除此之外，免疫球蛋白E（IgE）、嗜伊紅性白血球和陽離子蛋白（Eosinophilic cationic protein; ECP）等，都是參與氣喘發作的重要因子。過去的研究顯示 b2AR基因多型性與肺部的發育有關，IgE的產生與HLA-DR/-DQ基因有關，LTα（TNFβ；lymphotoxin-α）也被認為與IgE的產生有關，TNFα與呼吸道的高反應性或mucus分泌增加有關，然而TNF2.2基因型在東、西方人種間，分佈頻率是不同，是否TNF基因對氣喘的作用，在東、西方人種間是不同的？過去也很少研究是同時討論環境與遺傳因子交互作用，尤其在量化資料與肺功能變化的關係。
氣喘發作時，最明顯就是因呼吸道狹窄而肺功能下降，在過去有很多探討過敏與肺功能下降的研究，但是對於13-17歲，介於少年與年輕的成年人之間，且正處於發育變化最大的adolescents，其氣喘患者之肺功能變化仍是不清楚，相關的研究也不多，專門鎖定13-15歲的研究對象，我們幾乎沒有發現。我們過去的研究結果發現，國中氣喘學童有比非氣喘學童更低的肺功能，因此針對這一個族群，我們設計一系列研究，來嘗試了解國中氣喘學童，肺功能下降與哪些因子有關？是否遺傳感受性因子也參與其中。我們的研究方向有三個，分別如下：1）探討血中過敏原專一性IgE濃度與肺功能的相關性，2）探討嗜伊紅性白血球數目（EOS）與ECP濃度與肺功能的相關性，並進一步分析 b2AR的基因多型性，是否參與這樣的關係？3）探討HLA-DR/ -DQ基因和TNF基因多型性，與血中IgE量以及氣喘是否與有關？而這種相關性是否可反應到肺功能的改變？我們將就台南地區在1996年，完成隨機抽樣進行肺功能的檢測的學童，作為我們研究的毌群體，進行隨機抽樣後，對這些人寄出邀請信，邀請他們到成大醫院門診，進行氣喘的診斷與確認工作，並進行肺功能檢測工作，以自願方式，抽取學童1O ml的血液，進行五種常見過敏原之專一性IgE、總量IgE （sIgE）、Eosinophil數目（EOS）與ECP濃度的檢測工作，而β2AR、HLA-DR/-DQ與TNF基因多型性，則以聚合酵素鏈鎖反應 (polymerase chain reaction；PCR) 獲得。最後總共有80位氣喘學童，與69為非氣喘學童，完成所有的檢測。國中氣喘學童比非氣喘學童有較低的FEV1/FVC與adjusted FEF25-75% 和較高的Dermatophagoside farinae (Der f)、Dermatophagoside pteronyssinus（Der p）和German cockroach之專一性IgE濃度，與較高的sIgE、EOS和ECP濃度。當氣喘患者之Der f專一性IgE濃度＞100 IU/ ml或cockroach專一性IgE濃度＞0.7 IU/ ml時，比氣喘學童專一性IgE濃度＜0.7 IU/ ml，有更低的肺功能。同時，統計上的負相關性，也存在於這兩種專一性IgE濃度與肺功能間。EOS的上升與肺功能下降有關，但ECP濃度上升，則與肺功能下降無關。進一步依不同的β2AR基因多型性分組，在Arg/Arg16組，EOS的上升與肺功能下降有關；在Arg/Gly16組，情形類似但沒有達統計上的顯著，但在Gly/Gly16組，雖然沒有達統計上的顯著，反而是EOS上升，肺功能也是上升。在IgE與HLA-DR/-DQ的分析中，氣喘學童有較高的DR13基因出現頻率，DR13基因與較高濃度的Der p、Der f專一性IgE和sIgE，尤其是Der f。具有DR13基因的學童，比無DR13基因的學童，有較低的FEV1/FVC (P < 0.05) 與adjusted FEF25-75% (P < 0.05)。TNF基因多型性與氣喘無關，而DR13基因與LTαNcoI＊1 allele有遺傳連鎖，以多變項邏輯式回歸分析，並調整sIgE這項因素，我們發現DR13(+)/LTαNcoI＊1 haplotype (OR＝25.6，95％CI＝[2.2-1378]) 與sIgE > 100IU/ml (OR=6.1，95％CI＝[2.55-15.91] 都是氣喘的重要危險因子。
因此我們認為在氣喘沒有發作時，氣喘學童有較低的肺功能，對Der f 或cockroach過敏，是國中氣喘學童肺功能下降的重要因子。EOS的上升，與肺功能下降有關，但ECP濃度變化，則與肺功能下降無關，在不同β2AR基因多型性，可以觀察到EOS上升與肺功能下降的關係，是不大一致的。DR13基因與氣喘有關，也與高量的Der f專一性IgE和較低的肺功能有關，而較低的肺功能，應是透過高量Der f專一性IgE所致，DR13基因與LTαNcoI＊1間有遺傳上的連鎖，進一步分析其相對危險性，具有DR13(+)/LTαNcoI＊1 haplotype的學童，比不是這種haplotype的人有25.6倍的危險性，會有臨床上氣喘症狀。這些證據顯示，氣喘學童的肺功能下降，除了呼吸道的過敏與發炎反應之外，遺傳感受因子也扮演一個重要的角色；而且肺功能下降是環境與基因交互作用的結果。

The polymorphisms of β2-adrenergic receptor (b2AR), HLA-DR/-DQ genes, and tumor necrosis factor (TNF) gene cluster are recognized as important risk factors for asthma. IgE is known to play an important role in the pathogenesis of asthma. The TNFβ and HLA-DQ/DR genes were associated with IgE productions. Our knowledge about the growth of pulmonary function from childhood into early adulthood is incomplete. The relationships between serum levels of allergen-specific IgE and lung function in adolescents remain unclear. The inverse relationships between eosinophil counts (EOS)/ eosinophil cationic protein (ECP) and lung function remain controversial. The TNFα -308G/A frequency between Japanese and Caucasians in the UK was found different. It is possible that the roles of TNF genes in asthma were different between Asia population and Caucasians. Our previous unpublished data shows that asthmatics had lower lung function than nonasthmatics. We hypothesized that allergen-specific IgE, EOS, and genetic susceptibilities associated with lower lung function in asthmatics. We designed a series of experiments to determine 1) the association between serum levels of allergen-specific IgE and lower lung function, 2) the relationship between EOS/ ECP and lung function and the roles of b2AR genotypes within this relationship, 3) the association between HLA-DR/-DQ genes, TNF genes and serum IgE levels or asthma, and the relationship between those genes and lung function. We recruited a random sample of students from the nation-wide survey in Tainan city and county in 1996. The physician’s diagnosis and pulmonary function test were done in National Cheng Kung University hospital. We used different commercial kits of Pharmacia Cap system and Becton Dickinson Vacutainer System to determine the EOS, ECP, levels of allergen-specific IgE, and total serum IgE (sIgE). The genotypes were determined by polymerase chain reactions.
A total of 80 asthmatic and 69 nonasthmatic children completed this study. Asthmatics had lower FEF25-75% and FEV1/FVC. Asthmatics also had higher sIgE, ECP, and eosinophil counts in peripheral blood (EOS) than nonasthmatics. The sensitization rates to dust mite or German cockroach were higher in asthmatics than in nonasthmatics. Asthmatics with Dermatophagoides farinae (Der f)-specific IgE > 100 IU/ml or cockroach-specific IgE > 0.7 IU/ml showed lower pulmonary function. Lower lung function is correlated with an increase of EOS but not correlated with ECP. The inverse correlation between EOS and lung function was statistically significant in asthmatics with Arg/Arg16 or Gln/Glu27, non-significant but similar inverse correlation in asthmatics with Arg/Gly16 or Gln/Gln27, and non-significant but positive correlation in asthmatics with Gly/Gly16. We suggested that asthmatics had higher frequency of DR13 gene (OR = 8.6, 95% CI = [1.6-161]). DR13 gene is associated with higher sIgE and dust-mite-specific IgE, especially Der f. Children with DR13 gene had lower FEV1/FVC and adjusted FEF25-75%. No TNF haplotypes or genotypes were associated with asthma. DR13 gene was linked to LTαNcoI*1 allele. When sIgE was adjusted by multiple logistic regression, the risk of asthma was much higher in DR13(+)/ LTαNcoI*1 haplotype (OR = 25.6, 95% CI = [2.2-1378]) than in the others.
We concluded that during no asthma attack, asthmatics had lower lung function. Sensitization to Der f or cockroach was an important factor for asthmnatics with lower lung function. EOS was a better index of lower lung function than ECP. The inverse relationship between EOS and lung function can be differentiated by β2AR gene polymorphisms at amino acid 16. The DR13 gene was associated with high Der f-specific IgE and asthma. Children with DR13 had lower lung function attributed by high Der f-specific IgE productions. The DR13 gene is genetically linked with LTαNcoI*1 allele. The DR13(+)/LTαNcoI*1 haplotype had much higher risk of having clinical asthma symptoms than any other DR13/LTαNcoI haplotype. We suggest that allergic responses and inflammation in airway associate with lower lung function. The genetic susceptibility also played an important role in this relationship.

中文摘要I
AbstractIV
第一章 緒論1
第一節 氣喘的病理學與免疫反應2
第二節 氣喘與IgE4
第三節 氣喘與嗜伊紅性白血球和陽離子蛋白5
第四節 氣喘與肺功能下降6
第五節 氣喘與家族遺傳7
第六節 氣喘的遺傳感受性因子8
第七節 氣喘的流行病學研究11
第八節 氣喘與環境污染13
第九節 研究方向16
附表一 與氣喘相關的候選基因19
附圖一 過敏性氣喘的致病機轉20
附圖二 肺功能示意圖21
第二章 研究對象與方法22
研究族群與對象23
肺功能測試24
血液樣本的取得與保存24
過敏原專一性IgE的偵測24
EOS and ECP在血中含量的偵測25
DNA抽取26
PCR反應條件：β2AR genotyping27
PCR反應條件：HLA-DQB1/-DRB1 genotyping29
PCR反應條件：TNFα -308與LTαNcoI之基因多型性30
統計方法31
第三章 結果32
第一節 門診學童的基本資料33
第二節 氣喘與非氣喘學童之肺功能比較33
第三節 過敏原專一性IgE與肺功能34
氣喘與非氣喘學童之過敏盛行率之比較34
三種肺功能指標與過敏原專一性IgE量的關係 35
肺功能指標與過敏原專一性IgE濃度的相關性分析 36
第四節 EOS/ECP上升與肺功能下降的相關性，以及不同 b2AR基因多型性所扮演的角色36
氣喘與 b2AR基因多型性的關係36
血中ECP與EOS在氣喘與非氣喘學童之比較37
EOS/ECP與肺功能的相關性分析37
EOS 與肺功能的負相關在不同的 b2AR 基因多型性之分析37
第五節 血中IgE量或氣喘與HLA-DQ/-DR基因和TNF基因多型性的相關性分析38
血中IgE濃度在氣喘與非氣喘患者之比較38
HLA-DRB1與HLA-DQB1基因在氣喘與非氣喘學童的分佈38
IgE與HLA-DRB1/-DQB1基因間的關係 39
DR13基因與肺功能的關係39
TNF基因多型性與氣喘的關係39
TNF allele與 HLA-DR13基因的關係40
TNFα -308/LTαNcoI 基因多型性與IgE或肺功能的關係40
DR13/LTαNcoI*1 haplotype 與總量IgE對氣喘發生與否的
勝算比分析40
第四章 討論41
本研究的重要性42
過敏盛行率不同的可能解釋43
肺功能與過敏原專一性 IgE 關係的探討44
Der p 與 Der f 專一性 IgE 對肺功能的影響44
蟑螂專一性IgE對肺功能的影響45
貓毛或狗毛專一性IgE對肺功能的影響46
由肺功能指標變化，來看過敏原專一性IgE可能的影響46
EOS/ECP與肺功能相關性的比較47
B2AR基因多型性與氣喘關係的一致性47
B2AR基因多型性與種族間的關係48
EOS與肺功能關係在Gly16Gly基因型的變化48
HLA-DQB1/-DRB1基因分佈頻率，與IgE跟過去研究的比較49
HLA-DQB1*0502 基因與氣喘49
HLA-DRB1*07基因與氣喘49
DR13基因與IgE和氣喘50
DR13基因如何與較低肺功能有關50
DR13基因與LTα NcoI*1 allele 和總量IgE的相關性51
DR13/LTαNcoI＊1 haplotype可能扮演的角色51
DR13/LTαNcoI＊1 haplotype 與氣喘52
TNFα基因型與氣喘52
基因與環境的交互作用53
Asthma in remission的可能相關因子54
研究限制與解決方案 54
未來的研究方向56
第五章 結論58
第六章 參考文獻 60

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