| Abstract: | 過敏原 (allergen) 與香菸是具有產生反應性氧化產物 (reactive oxygen species [ROS])
的能力，因此可能貢獻至氣喘的發生上。抗氧化酵素超氧化物歧解酶 (manganese superoxide
dismutase [MnSOD]) 可能在發炎防禦機制上擔任要角，可將超氧化自由基 (superoxide
radicals) 轉化為過氧化氫 (hydrogen peroxide)；過氧化氫可能接續被骨髓性過氧化酶
(myeloperoxidase [MPO]) 轉變成次氯酸 (hypochlorous acid)，這可以造成上皮細胞的DNA
損傷。香菸可引起呼吸道上皮細胞發炎、減少上皮細胞的黏附以及增加分離，而細胞黏附
分子上皮細胞黏附蛋白 (E-cadherin) 對於正常結構以及上皮組織的功能之形成與維持，扮
演必要的角色；轉化生長因子 (Transforming growth factor [TGF])．β1可藉由對於白血球細
胞分化與抑制T淋巴球增生來對於發炎狀態進行調控。因此，超氧化物歧解酶 (MnSOD)、
骨髓性過氧化酶 (MPO)、人類上皮細胞黏附蛋白基因 (CDH1) 與TGF-β1基因可能相關於
氣喘的發生。在本研究中，我們選取115名氣喘兒童為病例以及230名非氣喘兒童為對照。
問卷訪視被執行以獲取人口學資料；兒童的室內二手菸暴露量是以每天暴露香菸支數計
算，亦即父母親於兒童在家時抽菸支數的總和。並以皮膚測試或是MAST (Multiple Antigen
Simultaneous Test) 檢驗台灣常見空氣過敏原之過敏反應；MnSOD、MPO、CDH1與TGF-β1
基因型則是以聚合酶鏈鎖反應 (polymerase chain reaction [PCR]) 判定。我們的結果顯示，
MnSOD Ala-Ala/Val-Ala基因型 (RRm = 2.1, 95% C.I. = 1.3-3.5)、CDH1 AA/CA基因型
(RRm = 2.6, 95% C.I. = 1.5-4.5) 與TGF-β1 TT/CT基因型 (RRm = 3.0, 95% C.I. = 1.3-6.5)，是
顯著相關於兒童氣喘發生危險。我們以過敏原測試陰性且攜帶MnSOD Val-Val基因型為參
考組 (RRm = 1.0)，則過敏原陰性且攜帶MnSOD Ala-Ala/Val-Ala基因型的兒童有3.4倍的氣
喘發生危險 (95% C.I. = 1.3-9.3)，過敏原陽性且攜帶MnSOD Val-Val基因型的兒童有6.6倍
的氣喘發生危險 (95% C.I. = 3.1-14.3)，過敏原陽性且攜帶MnSOD Ala-Ala/Val-Ala基因型的
II
兒童也有13.2倍的氣喘發生危險 (95% C.I. = 5.3-32.5)。相較於過敏原測試陰性且攜帶MPO
AA基因型的兒童，則過敏原陽性且攜帶MPO GG/GA基因型的兒童具有10.2倍 (95% C.I. =
1.3-82.5) 的氣喘發生危險。而過敏原陽性且攜帶CDH1 AA/CA基因型的兒童相較於過敏原
陰性且攜帶CDH1 CC基因型的兒童，具有19.9倍的氣喘發生危險 (95% C.I. = 4.6-87.0)；同
樣地相較於過敏原測試陰性且攜帶TGF-β1 CC基因型的兒童，則過敏原陽性且攜帶TGF-β1
TT/CT基因型的兒童具有30.4倍的氣喘發生危險 (95% C.I. = 3.8-243.4)。此外，在過敏原測
試陰性的兒童中，每天暴露香菸支數5支以上並且攜帶MnSOD Ala-Ala/Val-Ala基因型的兒
童，相較於每天暴露香菸支數0-5支並且攜帶MnSOD Val-Val基因型者具有7.1倍 (95% C.I. =
0.9-55.6, P = 0.06) 的氣喘發生危險。而每天暴露香菸支數5支以上並且攜帶CDH1 AA/CA
基因型的過敏原測試陰性的兒童，則較每天暴露香菸支數0-5支並且攜帶CDH1 CC基因型
的兒童具有8.5倍 (95% C.I. = 0.9-85.4, P = 0.07) 的氣喘發生危險。而每天暴露香菸支數5支
以上並且為TGF-β1 TT/CT基因型的過敏原測試陰性的兒童，也被觀察到具有10.0倍的氣喘
發生危險 (95% C.I. = 0.9-118.3, P = 0.07)，相較於每天暴露香菸支數0-5支並且攜帶TGF-β1
CC基因型的過敏原測試陰性之兒童。因此，MnSOD、MPO、CDH1與TGF-β1易感受性基
因型對於過敏原與室內二手菸暴露所導致的兒童氣喘發生，可能具有修飾作用。
Allergen and cigarette smoke could generate reactive oxygen species (ROS), and might
contribute to asthma. Manganese superoxide dismutase (MnSOD) involves inflammatory
defense and converts superoxide radicals into hydrogen peroxides. Hydrogen peroxide was
subsequently converted by myeloperoxidase (MPO) into hypochlorous acid and generalizes
DNA damages in epithelial cells. Cigarette smoke could cause respiratory epithelium
inflammation, decrease epithelial-cell adherence, increase detachment. E-cadherin is responsible
for the formation and maintenance of normal architecture and function of epithelial tissues.
Transforming growth factor [TGF]-β1 regulates inflammatory states by promoting leucocytes
differentiation and inhibiting T lymphocyte proliferation. Therefore, MnSOD, MPO, CDH1, and
TGF-β1 gene might be associated with the occurrence of asthma. In our study, we included 115
pediatric asthmatic children as cases and 230 non-asthmatic children as controls. Questionnaires
were administered to obtain demographic data. Environmental tobacco smoke (ETS) exposure
indicated number of cigarettes smoked daily from subject’s parents at home. Allergen test was
performed by intracutaneous skin test or Multiple Antigen Simultaneous Test with Taiwan
common aeroallergens. Polymerase chain reactions were conducted for MnSOD, MPO, CDH1
and TGF-β1 genetic polymorphisms. Our results showed that MnSOD Ala-Ala/Val-Ala
genotypes (matched relative risk [RRm] = 2.1, 95% C.I. = 1.3-3.5), CDH1 AA/CA genotypes
(RRm = 2.6, 95% C.I. = 1.5-4.5), and TGF-β1 TT/CT genotypes (RRm = 3.0, 95% C.I. = 1.3-6.5)
were significantly associated with the risk of childhood asthma. We selected allergen
test-negative children with MnSOD Val/Val genotype as reference (RRm = 1.0), allergen
test-negative children possessing MnSOD Ala-Ala/Val-Ala genotypes had a 3.4-fold risk of
asthma (95% C.I. = 1.3-9.3). For allergen test-positive children, those with MnSOD Val/Val
genotype had a 6.6-folds risk (95% C.I. = 3.1-14.3), whereas children carrying MnSOD
Ala-Ala/Val-Ala genotypes had a 13.2-fold risk of asthma (95% C.I. = 5.3-32.5). Compared to
IV
allergen test-negative children who carrying MPO AA genotype, allergen test-positive children
who carrying MPO GG/GA genotypes had a 10.2-folds risk of asthma (95% C.I. = 1.3-82.5).
Allergen-test positive children who carrying CDH1 AA/CA genotypes compared to allergen-test
negative children who carrying CDH1 CC genotype, had a 19.9 folds of asthma risk (95% C.I. =
4.6-87.0). Similarly, compared to allergen-test negative children who carrying TGF-β1 CC
genotype, allergen-test positive children who carrying TGF-β1 TT/CT genotypes had a
30.4-folds of asthma risk (95% C.I. = 3.8-243.4). In addition, among allergen test-negative
children, those exposed to more than 5 cigarettes daily and carrying MnSOD Ala-Ala/Val-Ala
genotypes, compared to those exposed to less than 5 cigarettes daily and carrying MnSOD
Val-Val genotype, had a 7.1-folds of asthma risk (95% C.I. = 0.9-55.6, P = 0.06). Allergen
test-negative children who exposed to more than 5 cigarettes daily and carrying CDH1 AA/CA
genotypes, compared to those exposed to less than 5 cigarettes daily and carrying CDH1 CC
genotype, had an 8.5-folds of asthma risk (95% C.I. = 0.9-85.4, P = 0.07). Allergen test-negative
children who exposed to more than 5 cigarettes daily and carrying TGF-β1 TT/CT genotypes,
also had a 10.0-folds of asthma risk (95% C.I. = 0.9-118.3, P = 0.07), compared to those exposed
to less than 5 cigarettes daily and carrying TGF-β1 CC genotype. Therefore, MnSOD, MPO,
CDH1 and TGF-β1 susceptible genotypes may moderate the occurrences of childhood asthma
induced by allergen and environmental tobacco smoke exposure. |
