臺灣博碩士論文加值系統

背景: 從肺泡界面活性蛋白質D基因剔除小鼠可以發現其肺部會有肺氣腫的變化；而肺氣腫是慢性阻塞性肺疾病人的肺部病理特徵之一。從觀察性的研究顯示，有部分慢性阻塞性肺疾病患並沒有明顯的致病相關危險因子。這進一步提出了基因的變異可能在慢性阻塞性肺疾致病的過程中扮演著一個重要的角色。我們研究對象為台灣男性族群，並假設肺泡界面活性蛋白質D之基因變異與血漿濃度可能和慢性阻塞性肺疾之致病過程與疾病相關表型有所關聯性。
方法: 研究為前瞻性、實驗對照組的設計方式，以成大醫院病人為對象，收納從2003年到2010年的個案。除了定量肺泡界面活性蛋白質D的血漿濃度外，另外我們從HapMap資料庫挑選了肺泡界面活性蛋白質D基因上的五個單核苷酸多態性位點做進一步的基因型相關統計分析。所有個案的基本資料與肺功能都會被記錄；而病患疾病之急性惡化頻率和追蹤的肺功能變化也會被觀察。此外；個案血漿中的細胞發炎激素也會被測量，而三年死亡率也會被分析。
結果: 總共有320位抽菸患者被收納 (其中有192位慢性阻塞性肺疾病患和128抽菸健康者)。我們發現肺泡界面活性蛋白質D的血漿濃度確實和慢性阻塞性肺疾患者的呼吸道阻塞程度與惡化頻率有正相關。進一步肺泡界面活性蛋白質D單型分析發現G-G-C-A單型有較低的風險會致病。如果對慢性阻塞性病患做次族群的分析，可以發現G-G-C-A單型的病患其血漿中有較低的肺泡界面活性蛋白質D濃度、較容易對支氣管擴張劑有所反應且疾病追蹤過程中有較好的肺功能改善；而且追蹤三年的存活分析顯示兩者間有所差異。
結論: 和過去的研究結果一致；我們的研究顯示肺泡界面活性蛋白質D之血漿濃度可以反應疾病的嚴重度。同時；肺泡界面活性蛋白質D的基因型變異對於慢性阻塞性肺疾的易感性與預後有所影響。

Background: Surfactant protein D (SFTPD) results in emphysema in knockout mice and emphysema is represented in the lung of patients with chronic obstructive pulmonary disease (COPD). From observational study results, a subgroup of patients develops COPD without obvious risk factors. It highlights the potential role of genetic susceptibility to the development of COPD. We hypothesized that generic variants and serum level of SFTPD may be associated in the pathogenesis of COPD and COPD-related phenotypes among Taiwanese.
Methods: A prospective, case-control and hospital-based study was designed from Jan 2003 to December 2010. In addition to quantification of SFTPD serum level, we picked up five single nucleotide polymorphisms (SNPs) of SFTPD from HapMap database for further genetic association analysis. Baseline demographic variables and degree of airflow obstruction were recorded. Frequency of exacerbation and change of lung function were assessed. Besides, inflammatory cytokines were also quantified. All-cause 3-year mortality was registered.
Results: There were 320 smokers enrolled in our study (192 COPD and 128 at-risk subjects). We found that the serum level of SFTPD did significantly positive correlate with the degree of airflow obstruction and frequency of exacerbation in COPD patients. Further haplotype association analysis revealed that haplotype G-G-C-A was correlated with lower risk of COPD. When we made subgroup analysis among COPD patients, those encompassing haplotype G-G-C-A had lower SFTPD serum level, easier positive response to bronchodilator and better improvement of lung function. 3-year survival analysis showed significant difference between groups in the long-term follow up.
Conclusions: Our study demonstrated the consistent results as previous investigation that the serum level of SFTPD may reflect the severity of disease. Meanwhile, the genetic variants of SFTPD had significant effect on the susceptibility and outcome of the disease.

Abstract in Chinese I
Abstract III
Acknowledgement V
Table contents VIII
Figure contents IX
Introduction 1
1. General introduction of chronic obstructive pulmonary disease 1
2. Characteristics and biological function of surfactant protein-D 2
3. Impact of surfactant protein-D on the chronic obstructive pulmonary disease 4
4. Hypothesis in our study 5
Material and methods 7
1. Study design and populations 7
2. DNA extraction and genotyping 8
3. Serum SFTPD concentration and measurement of biomarkers 10
4. Parameters for COPD-related phenotypes 11
5. Outcome evaluation 12
6. Statistical analysis 13
Results 15
1. Subject characteristics between COPD patients and healthy smokers 15
2. The correlation of SFTPD serum level with COPD severity 15
3. Allele and genotype frequency of SFTPD between COPD patients and healthy smokers 16
4. Haplotype analysis of SFTPD between COPD patients and healthy smokers 16
5. The association of SFTPD haplotype with COPD-related phenotypes 17
6. The effect of SFTPD haplotype on COPD 3-year survival 17
Discussion 19
References 25

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