- 學位論文
人類上皮細胞黏附蛋白 (CDH1) 和組織金屬蛋白水解酶抑制劑-1 (TIMP-1) 基因多形性與兒童氣喘之危險性
The human E-cadherin (CDH1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) genetic polymorphism and childhood asthma risk
摘要
兒童較成人容易發生氣喘 (asthma)，這是根源於遺傳及環境因素的共同作用。研究已經建議暴露到過敏原與環境二手菸 (environmental tobacco smoke) 是相關於易感受性個體之氣喘症狀。細胞黏附分子上皮細胞黏附蛋白 (E-cadherin) 在上皮組織的結構與功能之形成與維持上，扮演一個必要的角色。基質金屬蛋白水解酶 (matrix metalloproteinase [MMP]) 與金屬蛋白水解酶組織抑制劑-1 (tissue inhibitor of metalloproteinase-1 [TIMP-1]) 的平衡，亦是纖維化的關鍵指標；於MMP和TIMP表現之間的失衡可能導致組織重塑，進而產生肺部纖維化。因此，上皮細胞黏附蛋白 (cadherin-1 [CDH1]) 與TIMP-1基因可能相關於氣喘的發生；並且過敏原或室內二手菸暴露可能與CDH1以及TIMP-1基因對於兒童氣喘之發生具有交互作用效應存在。我們執行一項以醫院為基礎的病例對照研究，選取146名氣喘兒童為病例以及292名健康兒童為對照。個人特徵是經由問卷訪視所收集，CDH1與TIMP-1基因型則是以聚合酶鏈鎖反應 (polymerase chain reaction) 加以辨識。我們的多變項迴歸模式顯示父母親教育程度為大學 (matched relative risk [RRm] = 4.66; 95% confidence interval [C.I.] = 2.62-8.28) 或高中 (RRm = 1.90；95% C.I. = 1.09-3.31) 以上、氣喘家族史 (RRm = 2.79；95% C.I. = 1.70-4.54)、父母親抽菸狀況是不在家中抽菸者 (RRm = 0.60；95% C.I. = 0.39-0.91)、家中燒香 (RRm = 0.20；95% C.I. = 0.12-0.33)、家中從事紡織類工作 (RRm = 2.80；95% C.I. = 1.55-5.06)、過敏原測試陽性 (RRm = 3.17；95% C.I. = 2.25-4.48)、以及CDH1 A對偶基因 (RRm = 1.41；95% C.I. = 1.02-1.95)，顯著相關於兒童氣喘之發生。過敏原測試為陽性且攜帶CDH1 A對偶基因的兒童相較於過敏原測試為陽性且攜帶CDH1 C對偶基因的兒童，具有1.52倍的氣喘發生危險 (95% C.I. = 1.02-2.27)；進一步地，在過敏原測試為陽性的兒童中，每天於室內暴露香菸支數大於5支之CDH1 AA或CA基因型攜帶者相較於每天於室內暴露香菸支數0-5支之CDH1 CC基因型攜帶者，具有較高的氣喘發生危險 (RRm = 4.76；95% C.I. = 1.63-13.92)。此外，我們也觀察到CDH1與TIMP-1基因型對於兒童氣喘之發生是具有顯著的交互作用 (P = 0.007)。相較於過敏原測試為陰性且攜帶CDH1 C對偶基因的氣喘兒童，過敏原測試為陽性且攜帶CDH1 A對偶基因與C對偶基因的氣喘兒童，也分別具有顯著增加的血清免疫球蛋白 (immunoglobulin E [IgE]) 濃度與嗜伊紅性白血球數目；相似的結果也在TIMP-1基因中觀察到。因此，CDH1與TIMP-1基因在氣喘兒童之氣管重塑上扮演重要的角色。
並列摘要
Children are likely to develop asthma than adults, stemming from a combination of genetic and environmental causes. Studies have suggested that exposure to allergen and environmental tobacco smoke are related to asthmatic symptoms in susceptible individuals. The cellular adhesion molecule E-cadherin plays an essential role in the formation and maintenance of architecture and function of epithelial tissues. The balance of matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase-1 (TIMP-1) is also a critical index in the fibrosis. Imbalance in the expression of MMP and TIMP-1 might cause tissue remodelling and further result in the development of pulmonary fibrosis. Therefore, the cadherin-1 (CDH1) and TIMP-1 genes might be associated with the development of childhood asthma; and there are interaction effects between allergen or indoor tobacco smoke exposure with CDH1 and TIMP-1 genes on the development of childhood asthma. We conducted a hospital-based case-control study, 146 asthmatic children were selected as cases and 292 healthy children as controls. Questionnaire was applied to collect the personal characteristics. CDH1 and TIMP-1 genotypes were identified by polymerase chain reaction. Our multivariates regression model revealed that parents who had more than undergraduate (matched relative risk [RRm] = 4.66; 95% confidence interval [C.I.] = 2.62-8.28) and senior high school (RRm = 1.90; 95% C.I. = 1.09-3.31) education, family history of asthma (RRm = 2.79; 95% C.I. = 1.70-4.54), parental smoking habit as smoke outside home (RRm = 0.60; 95% C.I. = 0.39-0.91), incense burning at home (RRm = 0.20; 95% C.I. = 0.12-0.33), textile work at home (RRm = 2.80; 95% C.I. = 1.55-5.06), allergen test positive (RRm = 3.17; 95% C.I. = 2.25-4.48) and CDH1 A allele (RRm = 1.41; 95% C.I. = 1.02-1.95) were significantly associated with the development of childhood asthma. Children with allergen test positive and CDH1 A allele had 1.52 fold (95% C.I. = 1.02-2.27) increased risk for asthma development than those with allergen test positive and CDH1 C allele. Further, in the children with allergen test positive, CDH1 AA or CA genotype carriers who exposed to more than 5 cigarettes daily in indoor had a higher risk for asthma development (RRm = 4.76; 95% C.I. = 1.63-13.92), compared to CDH1 CC genotype carriers who exposed to 0-5 cigarettes daily in indoor. In addition, we also observed that CDH1 and TIMP-1 genotypes had a significant interaction on the occurrence of childhood asthma (P = 0.007). Compared to asthmatic children with allergen test negative and CDH1 C allele, those with allergen test positive and CDH1 A allele and those with allergen test positive and CDH1 C allele had significantly increased serum immunoglobulin E (IgE) level and eosinophil counts, respectively. Similar result was also observed in TIMP-1 genotypes. Therefore, CDH1 and TIMP-1 genes act important roles on airway remodelling of asthmatic children.