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研究生:李芃穎
研究生(外文):Lee,Pong-Ying
論文名稱:腎素-血管收縮素系統之基因多形性與慢性腎臟病之相關研究
論文名稱(外文):Genetic polymorphisms of the rennin-angiotensin system in chronic kidney disease
指導教授:蘇遂龍蘇遂龍引用關係
指導教授(外文):Su,Sui-Lung
口試委員:蘇遂龍周雨青盧國城
口試委員(外文):Su,Sui-LungChou,Yu-ChingLu,Kuo-Cheng
口試日期:2011-05-19
學位類別:碩士
校院名稱:國防醫學院
系所名稱:公共衛生學研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
語文別:中文
論文頁數:123
中文關鍵詞:慢性腎臟病腎素-血管收縮素系統血管收縮素原血管收縮素轉化酶血管收縮素II接收器第一型基因多形性
外文關鍵詞:Chronic kidney diseaseRenin angiotensin systemAngiotensinogenAngiotensin-1 converting enzymeAngiotensin II type1 receptorPolymorphism
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背景:台灣慢性腎臟病患日益增加,發生率及盛行率不斷的上升,盛行率為11.9%,慢性腎臟病惡化後所使用的替代療法佔用醫療資源越來越多。其中高血壓為慢性腎臟病重要因子,血壓升高會導致鈉的濃度降低,活化腎素-血管收縮素系統;而腎素-血管收縮素系統的基因多形性會驅使體內平衡至一個不正常的狀態,增加罹患慢性腎臟病的易感受性。因此本研究想要探討在台灣人群中,腎素-血管收縮素系統中血管收縮素原(AGT- C803T, T602C,A-20C)、血管收縮素轉化酶(ACE-A2350G)和血管收縮素II接受器第一型(AGTR1-A1166C,C573T,C-521T)的基因多形性,還有其他相關危險因子是否與慢性腎臟病具有相關性。
方法:本研究使採用病例對照研究設計,慢性腎臟病病例組來自天主教耕莘醫院,健康對照組則來自三軍總醫院健康檢查之民眾,腎絲球過濾率(GFR)小於60 ml/min/1.73m2為診斷標準,最後收取慢性腎臟病病例組有135名,健康對照組有270名,萃取其血液DNA再進行限制酶片段長度多形性,來確定其基因型。
結果:研究結果顯示,BMI、抽菸狀況、共伴疾病(高血壓、高血脂、糖尿病)及臨床生化值(BUN, creatinine, GFR, glucose, total cholesterol, triglyceride、收縮壓)與慢性腎臟病有顯著關聯。在腎素-血管收縮素系統基因多形性中,經邏輯式回歸分析控制其他變項後,ACE-A2350G中GG基因型與AA基因型進行比較,GG型對於慢性腎臟病為保護因子,統計上達顯著差異(OR=0.34, 95%CI: 0.15-0.78);再將慢性腎臟病分期,在ACE-A2350G慢性腎臟病第三期病人中,GG基因型是慢性腎臟病的保護因子(OR=0.23, 95%CI: 0.07-0.79),AGTR1-C573T中CT型對於慢性腎臟病為危險因子(OR=1.82, 95%CI: 1.07-3.09)。
結論:本研究結果顯示,在台灣人口中BMI、抽菸狀況、共伴疾病(高血壓、高血脂、糖尿病)及臨床生化值(BUN, creatinine, GFR, glucose, total cholesterol, triglyceride、收縮壓)為慢性腎臟病的危險因子,而ACE-A2350G與AGTR1-C573T基因多形性與慢性腎臟病有相關,這些因子可做為預測慢性腎臟病發生的危險因子。

Background: Chronic kidney disease (CKD) is highly prevalent in Taiwan and contributes to increased burden of disease in this population. In Taiwan, 11.9% of the general population is estimated to have CKD with the rate projected to increase. The impact of CKD on public health burden is worsening with increasing comorbidities and mortality, and huge medical expenses.Hypertension is the main contributor in the progression of renal failure with the presence or absence of proteinuria and is believed to be the major risk factor for the development of ESRD. It is also predicted that the prevalence of hypertension is increased with decreasing renal function due to a decrease in sodium excretion and activation of the Renin Angiotensin System (RAS). RAS polymorphisms alter the homeostasis to an abnormal state.The aim of the study was to assess the association of the gene polymorphism with CKD in Taiwanese.
Methods: The study group consisted of 135 patients with CKD from Cardinal Tien Hospital. The control group involved 270 healthy individuals from Tri-service General Hospital. All subjects were genotyped for the angiotensinogen (AGT-C803T, T602C, A-20C), angiotensin-1 converting enzyme (ACE-A2350G), and angiotensin II type1 receptor (AGTR1-A1166C, C573T, C-521T) polymorphisms of the RAS genes by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.
Results: Significant associations were observed in ACE-A2350G and AGTR1-C573T polymorphism between CKD patients and controls. In ACE-A2350G, the GG genotype compared with AA genotype was a protection against CKD (OR=0.34; 95%CI: 0.15-0.78). In AGTR1-C573T, the CT genotype compared with CC genotype was a risk towards CKD (OR=1.82; 95%CI: 1.07-3.09).
Conclusions: We conclude that ACE and AGTR1 polymorphisms were the likely candidate determinants of CKD. However, there was no association of AGT polymorphisms with susceptibility to CKD.

目錄 I
表目錄 III
圖目錄 V
中文摘要 VI
第一章 前言 1
第一節 研究背景 1
第二節 研究目的 4
第二章 文獻探討 6
第一節 慢性腎臟病 6
第二節 腎素-血管收縮素系統(RAS) 17
第三節 腎素-血管收縮素系統基因多形性 19
第三章 材料與方法 27
第一節 研究設計 27
第二節 研究資料之收集 29
第四節 研究架構 31
第五節 實驗方法 32
第四章 統計分析 43
第五章 結果 45
第一節 研究對象人口學背景資料 45
第二節 腎素-血管收縮素基因多形性之哈-溫平衡 48
第三節 腎素-血管收縮素系統基因多形性與慢性腎臟病相關性 50
第三節 腎素-血管收縮素系統單套型分析(Haplotype analysis) 82
第四節 RFLP分析結果 86
第六章 討論 93
第一節 與慢性腎臟病相關之危險因子 93
第二節 探討AGT基因多形性 95
第三節 探討ACE基因多形性 101
第四節 探討AGTR1基因多形性 103
第五節 探討RAS單套型 110
第六節 研究限制 112
第七章 結論與未來展望 113
第八章 參考文獻 115


表目錄
表1.美國腎臟基金會之慢性腎臟病分期標準 7
表2.AGT之基因多形性與病理狀態之相關性 21
表3.ACE之基因多形性與病理狀態之相關性 23
表4.AGTR1之基因多形性與病理狀態之相關性 26
表5.腎素-血管收縮素系統基因多形性位點與引子序列 37
表6.PCR試劑配置 38
表7.PCR反應條件 39
表8.RFLP反應試劑與條件 41
表9.慢性腎臟病病例組與對照組人口學變項與臨床生化值分布情形 47
表10.對照組RAS系統基因多形性之哈-溫平衡檢定 49
表11.慢性腎臟病病例組與對照組AGT-C803T基因型、對偶基因頻率與顯隱式模式分布 52
表12.慢性腎臟病病例組與對照組AGT-T602C基因型、對偶基因頻率與顯隱式模式分布 54
表13.慢性腎臟病病例組與對照組AGT-A-20C基因型、對偶基因頻率分布 56
表14.慢性腎臟病病人分期與對照組在AGT基因分布頻率 58
表15.慢性腎臟病病人分期與對照組在AGT基因邏輯式迴歸分析 61
表16.慢性腎臟病病例組與對照組ACE-A2350G基因型、對偶基因頻率與顯隱式模式分布 64
表17.慢性腎臟病病人分期與對照組在ACE基因分布頻率 66
表18.慢性腎臟病病人分期與對照組在ACE基因邏輯式迴歸分析 68
表19.慢性腎臟病病例組與對照組AGTR1-A1166C基因型、對偶基因頻率分布 70
表20.慢性腎臟病病例組與對照組AGTR1-C573T基因型、對偶基因與顯隱式模式頻率分布 73
表21.慢性腎臟病病例組與對照組AGTR1-C-521T基因型、對偶基因頻率與顯隱式模式分布 76
表22.慢性腎臟病病人分期與對照組在AGTR1基因多形性分布頻率 78
表23.慢性腎臟病病人分期與對照組在AGTR1基因邏輯式迴歸分析 81
表24.AGT單套型與慢性腎臟病的相關性分析 83
表25.AGTR1單套型與慢性腎臟病的相關性分析 85
表26.RAS基因多形性在不同種族中對偶基因之分布頻率 109


圖目錄
圖1.慢性腎臟病之末期腎病變發生率和盛行率之國際比較 2
圖2.RAS對於生理功能上的機轉 11
圖 3.慢性腎臟病與基因的關連性 16
圖4.RAS的生理功能機制圖 18
圖5.AGT基因多形性之連鎖不平衡檢定 83
圖6.AGTR1基因多形性之連鎖不平衡檢定 85
圖7.AGT-C803T基因多形性之瓊脂凝膠電泳圖 86
圖 8.AGT-T602CM基因多形性之瓊脂凝膠電泳圖 87
圖9.AGT-A-20C基因多形性之瓊脂凝膠電泳圖 88
圖10. ACE-A2350G基因多形性之瓊脂凝膠電泳圖 89
圖11.AGTR1-A1166C基因多形性之瓊脂凝膠電泳圖 90
圖12. AGTR1-C573T基因多形性之瓊脂凝膠電泳圖 91
圖13. AGTR1-C-521T基因多形性之瓊脂凝膠電泳圖 92


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