臺灣博碩士論文加值系統

痛風（gout）為一群因尿酸鹽或尿酸之晶體沉積於組織之病變的總稱，其臨床的表現主要包括了痛風性關節炎（gouty arthritis）、痛風石（tophus）、痛風性腎臟病變（gouty nephropathy）與尿路之尿酸結石（uric acid calculus in the urinary tract）。根據統計調查及文獻研究，發現男性罹患痛風比率要比女性高出許多倍，除了生活環境、飲食型態的不同所致，遺傳因素可能是主要原因，但是其中的機制未明仍要更進一步討論及研究。因此，本研究探討細胞激素單核苷酸多型性 (single nucleotide polymorphism, SNP) 與罹患痛風疾病是否有相關性存在；雄性激素接受體（androgen receptor, AR）、雌性激素接受體（estrogen receptor, ER）多型性是否與影響男女罹患痛風的比例有關。所探討之標記基因包括interleukin-1（IL-1β promoter、IL-1βexon5、IL-1 Ra）、interleukin-4（promoter、intron 3）、tumor necrosis factor alpha （TNF-α）-308，我們利用polymerase chain reaction（PCR）的方式研究痛風患者196位和正常人的基因多型性，除了欲了解基因多型性在正常人與痛風病患分佈是否不同，與發病率是否有關；並且透過基因定序分析比較痛風患者與正常對照組在雄性激素接受體、雌性激素接受體基因座內的核苷酸重複序列數目是否有差異，重複序列的多寡是否影響痛風發病機率。
資料分析藉由SPSS10.0版本軟體進行統計分析。研究結果發現，痛風病患與正常對照組細胞激素之IL-1（IL-1β promoter、IL-1β exon5、IL-1 Ra）、IL-4（promoter、intron 3）、TNFα-308，無論在基因型分佈、對偶基因頻率、對偶基因攜帶率均無明顯的差異性；另外將痛風病患與各基因多型性之臨床表現影響作分析，我們發現IL-1β exon 5 及TNFα在高三酸甘油酯血症（Hypertriglyceridemia）具顯著相關性，也就是說當高三酸甘油酯血症之疾病患者同時具有IL-1β exon 5 E2基因多型性（即E1/E2基因型），可促使痛風的發生；當高三酸甘油酯血症之疾病患者同時具有TNFα A基因多型性（即G/A基因型），可促使痛風的發生；亦可說IL-1β exon 5 E2基因多型性及TNFα A基因多型性是導致痛風之危險因子，而IL-1β exon 5 E1基因多型性及TNFα G基因多型性是保護因子。在作基因定序分析比較後，雖然痛風患者基因座內(CAG)n三聯核苷酸、(TA)n雙聯核苷酸重複序列數目都在正常範圍，但我們發現雄性激素接受體在痛風病患與正常對照組沒有顯著差異，而雌性激素接受體在痛風病患與正常對照組則有顯著差異（P＜0.005）；當痛風病患之(TA)n雙聯核苷酸重複序列數目介於10-15次罹患痛風的可能性，是(TA)n雙聯核苷酸重複序列數目介於16-21次罹患痛風可能性的1.75倍、(TA)n雙聯核苷酸重複序列數目介於22-27次罹患痛風可能性的29倍；也就是說當(TA)n雙聯核苷酸重複序列數目愈少，罹患痛風比率愈高，可見(TA)n雙聯核苷酸具保護作用。由以上結果得知IL-1β exon 5 、TNFα及雌性激素基因多型性與痛風具顯著相關性，將可提供作為痛風預測之基因標記。

Gout is not a single disease but a term used to describe a group of metabolic disorders characterized by tissue deposition monosodium urate (MSU) monohydrate crystals from hyperuricaemic body fluids. Major clinical manifestations include gouty arthritis, tophus, gouty nephropathy, and uric acid calaulus in the urinary tract. According to epidemiological and experimental studies, the incidence of gout is higher in men than in women. In addition to life style and eating habits, genetic factors are probably the major cause of the disease, although the exact mechanism remains to be determined. The purpose of this study was to examine whether single nucleutide polymorphisms (SNPs) of the IL-1（IL-1β promoter, IL-1βexon5, IL-1 Ra）, IL-4 and tumor necrosis factor alpha （TNFα-308）gene polymorphisms, the CAG repeats in the AR gene and the TA repeats in the ER gene were associated with gout. This study included 196 gout patients and health individuals as control subjects. Amplification of the gene markers was carried out by polymerase chain reaction (PCR). The amplified products were analyzed by restriction fragment length polymorphism (RFLP) and sequence analysis.
We used SPSS10.0 to perform statistical analysis upon the data collected. No significant differents were observed in the genetic distribution, allelic frequencies or allele carriage rates of the IL-1（IL-1β promoter, IL-1βexon5, IL-1 Ra）, IL-4 and TNFα-308 gene between patients with gout and health control subjects. Additionally, we did not detect any association between IL-1(IL-1β promoter, IL-1βexon5, IL-1 Ra), IL-4 and TNFα-308 genotypes and the clinical and laboratory profiles in gout patients, except for hypertriglyceridemia. There were significant differences in the IL-1βexon 5 genotype and TNFα-308 polymorphisms between gout patients with and without hypertriglyceridemia. It was found that IL-1βexon 5 E2 gene polymorphism can trigger gout in patient with hypertriglyceridemia. It was also noted that the TNFαA gene polymorphism can trigger gout in patient with hypertriglyceridemia. While both IL-1βexon 5 E2 and TNFαA seen to cause gout, both IL-1βexon 5 E1 gene and TNFαG genes are protective factors. Associations between gout and the CAG repeats in the AR gene and the TA repeats in the ER gene were evaluated. There were no statistical differens between gout patients and the normal controls in the distribution of CAG repeats in the AR gene. But, there was a significant difference between gout patients and the normal controls in the distribution of TA repeats in the ER gene. The risk of gout in patients with 10-15 TA dinucleotide repeats is 1.75-fold and 29-fold of that in patients with 16-21 TA dinucleotide repeats and 22-27 TA dinucleotide repeats, respectively. In other words, the fewer number of TA dinucleotide repeats, the higher the rate of coming down with gout.
The results of our study suggest that the IL-1βexon 5、TNFα-308 and estrogen receptor gene polymorphisms are associated with gout, and they may be candidate genetic markers for risk of gout.

目錄 頁碼
中文摘要 1
英文摘要 3
壹、前言 5
貳、文獻探討 6
一、何謂尿酸及高尿酸血症之定義 6
二、痛風的定義 8
三、痛風及其相關危險因子之探討 10
參、研究動機 16
肆、基因多型性 17
一、單一核苷酸多型性﹙SNP﹚ 17
二、細胞激素與基因多型性 18
三、痛風與細胞激素多型性之關係 23
四、雄性激素接受體 24
五、雌性激素接受體 27
伍、材料與方法 29
一、材料 29
二、方法 30
（1）DNA 萃取 30
（2）聚合酶鏈鎖反應 31
（3）膠體電泳法 34
（4）限制片段長度多型性分析 35
（5）DNA定序 36
三、統計結果分析 37
陸、結果 38
一、IL-1β promoter-511的基因多型性分析 38
二、IL-1β exon 5的基因多型性分析 38
三、IL-1 Ra intron 2的基因多型性分析 39
四、IL-4 promoter-590的基因多型性分析 39
五、IL-4 intron 3的基因多型性分析 40
六、TNF-α的基因多型性分析 40
七、AR的基因多型性分析 41
八、ER的基因多型性分析 41
柒、小結 43
捌、討論 44
玖、未來研究建議 50
參考文獻 51
附表 68
表一、問卷調查 68
表二、統計表 69
表三、偵測IL-1、IL-4、TNF、Androgen receptor、Estrogen receptor基因多型性之聚合酶連鎖反應使用之引子對及切點分析之條件 70
表四（A）、痛風病患及正常對照組之IL-1b promoter、IL-1b exon5基因型分佈、對偶基因之頻率和攜帶率分析 71
表四（B）、痛風病患在IL-1β promoter、 IL-1βexon5及IL-1 Ra基因 72
多型性之臨床表現影響比較
表五（A）、痛風病患及正常對照組之IL-1RA基因型分佈、對偶基因之 73
頻率和攜帶率分析
表五（B）、痛風病患在IL-1 RA基因多型性之臨床表現影響比較 74
表六（A）、痛風病患及正常對照組之IL-4 promoter、IL-4 intron3基因型 75
分佈、對偶基因之頻率和攜帶率分析
表六（B）、痛風病患在IL-4 promoter 、IL-4 intron-3基因多型性之臨床 76
表現影響比較
表七（A）、痛風病患及正常對照組之TNF-alpha基因型分佈、對偶基因 77
之頻率和攜帶率分析
表七（B）、痛風病患在TNF-α基因多型性之臨床表現影響比較 78
表八、痛風患者與正常對照組在雄性激素接受體基因座內的(CAG)n重 79
複次數平均值、P值與統計分析
表九（A）、痛風患者與正常對照組在雌性激素接受體基因座內的(TA)n 80
重複次數平均值、P值與統計分析
表九（B）、痛風患者與正常對照組在雌性激素接受體基因座內的(TA)n 81
重複次數平均值、P值與統計分析
表十（A）、(CAG)n重複次數對雄性激素接受體基因多型性和痛風關係 82
的影響
表十（B）、(CAG)n重複次數對雄性激素接受體基因多型性和痛風關係 83
的影響
表十一（A）、(TA)n重複次數對雌性激素接受體基因多型性和痛風關係 84
的影響
表十一（B）、(TA)n重複次數對雌性激素接受體基因多型性和痛風關係 85
的影響
附圖 86
圖一、第一白血球介素β啟動子基因多型性的凝膠電泳圖 86
圖二、第一白血球介素β第五外插序列基因多型性的凝膠電泳圖 87
圖三、第一白血球介素受體拮抗者基因多型性的凝膠電泳圖 88
圖四、第四白血球介素啟動子基因多型性的凝膠電泳圖 89
圖五、第四白血球介素β第三內插序列基因多型性的凝膠電泳圖 90
圖六、腫瘤壞死因子α啟動子基因多型性的凝膠電泳圖 91
圖七、AR基因CAG重複片段多型性鑑定 92
圖八、ER基因TA重複片段多型性鑑定 93
圖九、男性痛風患者與正常對照組在雄性激素接受體基因座內的(CAG)n 94
三聯核苷酸重複序列之分佈情形
圖十、女性痛風患者與正常對照組在雄性激素接受體基因座內的(CAG)n 95
三聯核苷酸重複序列之分佈情形
圖十一、痛風患者與正常對照組在雌性激素接受體基因座內的(TA)n雙聯 96
核苷酸重複序列之分佈情形
圖十二、男性痛風患者與正常對照組在雌性激素接受體基因座內的(TA)n 97
雙聯核苷酸重複序列之分佈情形
圖十三、女性痛風患者與正常對照組在雌性激素接受體基因座內的(TA)n 98
雙聯核苷酸重複序列之分佈情形
縮寫表 99

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