血中一氧化氮濃度與遺傳因素對於
成人氣喘及肺功能之相關性

研究背景: 氣喘在世界各地對於個人健康或家庭影響外，也造成醫療健康照護系統及政府的負擔。氣喘的發生與基因及環境有關，已知一氧化氮（NO）在氣喘病人上表現出較高的濃度，而一氧化氮的生成量與NOS(一氧化氮合成酶)基因及ARG(精氨酸酶)基因有關，NOS 基因會催化Arginine(精氨酸)使其產生內生性一氧化氮(NO)，ARG 基因則會和NOS 競爭Arginine，降低NO 的生成。關於氣喘及基因多型性影響NO 濃度之間的相關文獻仍很少見。研究目標: 本研究欲了解ARG 的基因多型性對於一氧化氮、肺功能及氣喘的影響、以及一氧化氮濃度與氣喘相關症狀（肺功能下降）之間的關係，以及環境因子與氣喘之間的相關。期待可以篩選出與氣喘相關的易感受基因，及生活中的環境因素，藉以事先預防接觸過敏原，降低氣喘的發生。材料方法: 本研究以橫斷式(cross-sectional study)研究設計，分別從高雄醫學大學附設中和醫院胸腔科門診收集氣喘組87名，及以1:1~1:3配對年齡、性別及種族的方式，在高雄市新上社區收集對照組199名，共286位成人（18 歲以上）為研究對象，並建立收集所有個案的問卷基本資料檔及血液，以測定過敏指標、進行基因型判定。研究結果：本研究分析氣喘組與對照組，在基本人口學變項中年齡、目前就職行業、抽菸比例、有二手菸暴露比例，及環境因子及過敏體質變項，家中有出現蟑螂、家中有燒香拜拜習慣、過敏體質、過敏性鼻炎、父親是否罹患氣喘、母親是否罹患氣喘、家族氣喘史（父母親任一為氣喘者）、手足是否罹患氣喘等變項皆具統計學上顯著意義(P＜0.05)。在氣喘相關症狀的變項中，血清中 total IgE 平均濃度較高(325.81±653.19 kU/l 及128.07 ±358.94 kU/l)、經由log 轉換後其值也較高（2.08±0.66 及 1.59±0.63）、原始測量值指標FEV1_b、FVC_b、FEV1/FVC_b 較低（FEV1_b：1.68±0.68 L 及2.40±0.72L ; FVC_b：2.26±0.76L 及 2.79±0.78L ;FEV1/FVC_b：0.74± 0.15 及 0.86±0.12），常模預測值指標FEV1%_p、FVC%_p、FEV1/FVC_p 較低（FEV1%_p：68.33±19.84﹪及91.22±19.46﹪ ; FVC%_p：84.28±22.71 ﹪及 97.23±18.57﹪ ;FEV1/FVC_p：0.83±0.21 及 0.94±0.14）血清中一氧化氮(NO)的量較高（27.54±24.45 μmol/L 及 20.27±14.79μmol/L），且上述變項於兩組間之差異皆已達統計學上顯著意義(p＜0.05)。在校正年齡與性別之後，進行NO 濃度與IgE 濃度的交互作用分析時，可看出NO 濃度低與IgE 濃度高者相較於NO 濃度與IgE 濃度皆低者其氣喘危險性分別為4.699 倍（95%CI: 2.103-10.500，p=0.000），NO 濃度高=與 IgE 濃度皆高者相較於NO 濃度與IgE 濃度皆低者其氣喘危險性分別為7.551 倍（95%CI: 3.064-18.606，p=0.000）。若以ARG-S1 基因 CC 型及NO 低濃度為參考組，ARG-S1 基因CT/TT 型與NO 高濃度存在交互作用，其氣喘危險性為2.860 倍（95%CI: 1.119-7.309，p=0.028）具有顯著意義；若以ARG-S1 基因 CC 型及IgE 低濃度為參考組，ARG-S1 基因CT/TT 型與IgE 高濃度亦存在交互作用，其氣喘危險性為11.112 倍（95%CI:4.538-27.207，p=0.000）具有顯著意義；而若以ARG-S1 基因 CC 型及無抽菸習慣為參考組，ARG-S1 基因CT/TT 型與有抽煙習慣，其氣喘危險性為3.410 倍（95%CI:1.251-9.296，p=0.016）具有顯著意義。結論: 在本篇研究中， ARG 的基因多型性對於與氣喘相關症狀（肺功能下降）之間的關係，具有顯著的相關。顯示其在氣喘的致病機轉中扮演一個重要的角色。且根據交互作用分析的結果，具有ARG-S1 易感受性基因型（CT/TT），同時NO 及Total IgE 處於高濃度的狀況下，其氣喘的危險性亦可以觀察到顯著的升高。不僅僅如此，NO 濃度與Total IgE 和抽煙習慣也同樣的存在交互作用。因此ARG 的基因多型性可以當作氣喘的危險因子之ㄧ。未來可以針對基因多型性造成酵素功能上的差異，或是其他與發炎反應相關的因子，做更深一層的探討。

關鍵字

氣喘；肺功能；成人；一氧化氮；遺傳因素

並列摘要

Background: Asthma has the impact on individual health or family around the world. Besides, it becomes a burden on the medical health care system and the government. Asthma is relevant to the gene and the environment. And it is known that asthma patients show the higher NO consideration; the NO production is relevant to NOS gene and ARG gene. NOS gene enable to catalyze Arginine to produce endogenous NO while ARG gene will compete with Arginine to decrease the NO production. It was still the rare studies which are processed to explore the relation between Asthma and polymorphism. Objective： Our research would like to realize the influence of ARG polymorphism on NO, lung function and asthma, and the relation between the NO consideration and the relevant symptom of asthma, and the correlation between the environmental factors and asthma. We expect to sift out the acceptant gene relating to the asthma and the environmental factors around life, and then prevent the allergen in advance and then decreeing asthma to happen. Materials and Methods： Our study was taken by cross-sectional study in Kaohsiung City, Taiwan. 199 controls were selected from ribcage out-patient Kaohsiung Medical University Chung-Ho Memorial Hospital and Sinshang community, Kaohsiung City. The amount of subjects who were 18 years old and upward was 286, 87 subjects with asthma, and the others without it. The control group was selected by matching age and gender, and proportion was 1:1 ~ 1:3. We established and collected the questionnaires about personal information and blood samples of all cases. And then, total IgE and phadiatop were measured atopic index and genotyping. Result： The data which analyzed the asthmas under controlled situation showed that age, BMI, career, smoking percentage and exposing to secondhand smoke had statistically significant association . In environmental factors, the data showed that cockroach and Chinese incense had statistically significant association as well. In allergic physique factors, the data showed allergic physique, allergic rhinitis, if a parent was affected to asthma, the familial history of affecting asthma （one of the parents was asthmatic）and if siblings were affected to asthma had statistically significant association(p＜0.05). In the relevant symptom of asthma factors, the total IgE consideration was higher on average(325.81±653.19 kU/l and 128.07±358.94 kU/l). After transforming to log number, it was still higher（2.08±0.66 and 1.59±0.63）.The original measure index including FVE_b1, FVC_b and FVE1/ FVC_b were lower(FEV1_b：1.68±0.68 and 2.40±0.72L; FVC_b： 2.26±0.76L and 2.79±0.78L; FEV1/FVC_b：0.74±0.15 and 0.86±0.12). The index of lung function FEV1% and FVC% were lower（FEV1%: 68.33±19.84 and 91.22±19.46; FVC%:84.28±22.71 and 97.23±18.57; FEV1/FVC%：0.83±0.21 and 0.94±0.14）. NO in the blood serum had high quantity （27.54±24.45μmol/L and 20.27±14.79μmol/L）. In addition, the factors as above had significant association on the difference between the asthmas and the controls. The interaction between the high IgE concentration and the NO high concentration was significant. The risk of Asthma in the group with higher NO and IgE concentration was the multiplier of 4.699 than the group with low NO and high IgE concentration（95%CI: 2.103-10.500，p=0.000）, and multiplier increases to 7.551 comparing the group with higher NO and IgE concentration and the lower concentration group（95%CI: 3.064-18.606，p=0.000）. Take ARG-S1 gene and low NO concentration as reference group, there is interaction between ARG-S1 gene CT/TT type and high NO concentration, and the multiplier is 2.860 than reference group with statistical signicance（95%CI: 1.119-7.309，p=0.028） . While take ARG-S1 gene CC type and low NO concentration as reference group, there is still interaction and the multiplier is 11.112 than the reference group with statistical signicance （95%CI:4.538-27.207，p=0.000）. Take ARG-S1 gene CC type and non-smoking habits as reference group, theARG-S1 CT/TT type and smoking habits result in higher risk of asthma up to 3.410 times to reference group and as well with statistical significance. （95%CI:1.251-9.296，p=0.016）. Conclusion： In this research , the ARG polymorphism and the relative symptom （Lung function decrease）had the significant relation which showed they played the important role in the fateful crisis. And according to the result of interaction analysis, with the ARG-S1 acceptable gene（CT/TT）and under the condition of high NO and Total IgE at same time, the danger of asthma would also be higher. Moreover, there is still interaction between NO and Total IgE with the habit of smoking. Thus, ARG polymorphism could be one of the risk factors of asthma. In the future, we can have advanced research on polymorphism causing the difference in enzyme activity or other relevant factors in phlogistic reaction.