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研究生:呂蕙均
研究生(外文):Hui-Chen Lu
論文名稱:探討台灣族群鈣離子通道基因多型性在慢性腎臟疾病發展和紅血球生成素阻抗之角色
論文名稱(外文):The Association Study between Genetics Polymorphism of Calcium Channel Transporters and the Progression of Chronic Kidney Disease and EPO Resistance in Taiwanese Population
指導教授:張偉嶠
指導教授(外文):Wei-Chiao Chang
口試委員:黃尚志沈麗娟簡淑真
口試委員(外文):Shu-Chen Chien
口試日期:2015-06-20
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:臨床藥物基因體學暨蛋白質體學碩士學位學程
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:中文
論文頁數:127
中文關鍵詞:慢性腎臟疾病末期腎臟疾病基因多型性慢性腎臟疾病發展紅血球生成素阻抗性微陣列
外文關鍵詞:chronic kidney diseaseend-stage renal diseasespolymorphismCKD progressionEPO resistancemicroarray
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臺灣的慢性腎臟疾病和末期腎臟疾病發生率及盛行率在世界各國中始終名列前茅,同時也是台灣人口前十大死因之一。雖然慢性腎臟疾病在台灣的治療已十分完善,在臨床上仍然觀察到一些慢性腎臟病患者病情迅速惡化與腎性貧血患者出現紅血球生成素阻抗性,其原因到目前為止尚未十分清楚。先前的研究指出鈣離子通道的單一核苷酸基因多型性與慢性腎臟疾病有關,鈣池調控型通道的Orai1參與T細胞以及腎小球細胞等非興奮性細胞之鈣池調控鈣離子流入(Store -Operated Calcium Entry, SOCE),而TRPC3、TRPC4主要參與經受體調控型通道(Receptor-Operated Ca2+ Channel, ROC)引發之鈣離子流入,TRPV5則是體內腎臟鈣離子吸收和再吸收的運輸通道,除了鈣離子運輸外,這些鈣離子通道在發炎反應中亦扮演重要角色。因此,本研究對ORAI1、TRPC3、TRPC4、TRPV5基因多型性與慢性腎臟疾病發展、紅血球生成素阻抗性之相關性進行探討。結果顯示,TRPC3 (rs 10518289)及TRPC3 (rs 906493)皆在基因型分型、顯性遺傳以及對數加成模式與罹患慢性腎臟疾病病人的腎絲球過濾率快速下降有統計上的顯著相關性,這兩個位點分別帶C等位基因(Allele)時GFR可能會下降得較快;另外TRPC3 rs11732666則與紅血球生成素阻抗性有相關性,當病人的rs11732666帶C等位基因(Allele)時會有較高風險產生紅血球生成素阻抗性,故需使用較高劑量之紅血球生成素才能達到療效,本研究顯示TRPC3的基因型變異可能會影響慢性腎臟病的惡化和紅血球生成素阻抗性的產生。
In Taiwan, chronic kidney disease (CKD) and end-stage renal diseases (ESRD) have relatively high incidence and prevalence worldwide. These diseases are also the tenth leading cause of death in Taiwan. The decreasing of glomerular filtration rate (GFR) and increasing of albuminuria are associated with risk of cardiovascular events and all-cause mortality. Although the treatment of CKD in Taiwan has been comprehensively established, some CKD patients with anemia were observed with resistance to high dosage of recombinant human erythropoietin (EPO). Besides, some of them get worse rapidly with unclear reason. Previous studies have indicated that Ca2+ channel transporter genes such as Orai1 and TRPCs are associated with kidney disease and erythropoietin. Orai1 is one of Store-Operated Ca2+ Channel (SOCs) which takes part in store-operated Ca2+ entry (SOCE) on non- excitable cells. TRPC3 and TRPC4 are members of transient receptor potential cation channel super family, and play the role of receptor-operated Ca2+ entry. Furthermore, TRPV5 modulates the absorption and reabsorption of Ca2+ in kidney. These four calcium channel transporters above not only modulate the calcium influx but also involve in inflammation and immune system. Therefore, we conduct a study to figure out the association between polymorphism of calcium channel transporter genes and disease progression as well as EPO resistance among patients with CKD. The results show that two single nucleotide polymorphisms (SNPs) of TRPC3, rs10518289 and rs906493 are significantly associated with the decline of GFR. In addition, our results indicate rs11732666 of TRPC3 is significantly associated with EPO resistance. These findings suggest that the progression of CKD and EPO resistance could be predicted by screening polymorphism of TRPC3.
表目錄 ………………………………………………………………………………8
圖目錄 ………………………………………………………………………………9
中文摘要 10
ABSTRACT 11
壹、 緒論 12
一、 慢性腎臟疾病(CHRONIC KIDNEY DISEASE,CKD) 12
(一) 何謂慢性腎臟疾病 12
(二) 慢性腎臟疾病死亡風險因子 13
(三) 全球慢性腎臟疾病之趨勢 14
(四) 台灣地區慢性腎臟疾病之流行病學 1
(五) 慢性腎臟疾病引起之腎性貧血(RENAL ANEMIA) 17
(六) 慢性腎臟疾病的易感性基因(GENETICS SUSCEPTIBILITY TO CHRONIC KIDNEY DISEASE) 18
(七) 微陣列 (MICROARRAY) 19
二、 鈣池調控鈣離子通道(STORE-OPERATED CA2+ CHANNEL, SOC) 21
三、 受體調控型通道(RECEPTOR-OPERATED CHANNEL, ROC) 23
一、 病患篩選(PATIENT RECRUITMENTS) 28
二、 DNA萃取(DNA EXTRACTION) 30
三、 單一核苷酸基因多型性選擇條件(SINGLE NUCLEOTIDE POLYMORPHISM SELECTION) 32
五、 周邊血液單核球分離(PERIPHERAL BLOOD MONONUCLEAR CELL ISOLATION) 37
六、 RNA 萃取(RNA EXTRACTION) 39
七、 微陣列分析(MICROARRAY ANALYSIS) 41
八、 統計學分析(STATISTICAL ANALYSIS) 43
参、第一節 鈣離子通道基因多型性與慢性腎臟疾病發展之相關性 44
一、 研究背景 44
二、 結果 49
三、 結論 53
四、 討論 54
一、 研究背景 57
二、 結果 62
三、 結論 67
四、 討論 68
肆、 參考文獻 72
伍、 圖表 96
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