跳到主要內容

臺灣博碩士論文加值系統

(3.238.135.174) 您好!臺灣時間:2021/08/05 07:02
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

: 
twitterline
研究生:潘文正
研究生(外文):Wen-Cheng Pan
論文名稱:台灣地區慢性C型肝炎病患與變形成長因子基因多形性之關係
論文名稱(外文):Transforming growth factor-B1 gene polymorphisms in Taiwanese patients with chronic hepatitis C treated with combined interferon and ribavirin therapy
指導教授:莊萬龍莊萬龍引用關係
指導教授(外文):Wan-Long Chuang
學位類別:碩士
校院名稱:高雄醫學大學
系所名稱:醫學研究所碩士班
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:2005
畢業學年度:93
語文別:中文
論文頁數:38
中文關鍵詞:變形成長因子-B 1慢性C型肝炎甲型干擾素
外文關鍵詞:chronic hepatitisTransforming growth factor-B1
相關次數:
  • 被引用被引用:0
  • 點閱點閱:185
  • 評分評分:
  • 下載下載:23
  • 收藏至我的研究室書目清單書目收藏:0
TGF-��1(transforming growth factor- ��1)能促進活化肝星狀細胞(Hepatic stellate cells)及製造細胞外間質蛋白質(extracellular matrix proteins)而導致慢性C型肝炎病患的肝臟纖維化,TGF-��1的製造主要在於基因的控制,特別與基因的多形性有關。最近的研究發現在TGF-��1基因上兩個位置,分別是+ 29 (codon 10)和+ 74 (codon 25),似乎與肝臟纖維化有關,並且可能影響抗病毒藥物的療效。
本研究的目的在於探討慢性C型肝炎病患TGF-��1基因多形性在codon 10和codon 25之分布情形以及與病患體內C型肝炎病毒基因型,病毒濃度,肝臟發炎程度之關係,及其對干擾素合併ribavirin治療慢性C型肝炎療效之影響。共收集145位慢性C型肝炎病患進入此研究(男性90位,女性55位,平均年齡47.1�b 11.3歲) ,全部病患血清anti-HCV及HCV RNA均呈陽性而HBsAg均呈陰性,病理切片根據HAI (Histological activity index)和兩位病理醫師協助下,將肝臟發炎程度予以分類,其中14位呈現肝硬化現象。血清HCV RNA的定性檢查是以Cobas Amplicor HCV test 2.0測試。HCV基因型乃以Okamoto等人所發展之方法測定,此方法可檢測出1a、1b、2a、2b及3a等五種HCV基因亞型。病毒基因型分型為1b型65 位(44.8%),2a型43位(29.7%),2b型17位(11.7%)混合型5位(3.5%)及無法分型者15位(10.3%)。血清HCV RNA定量則以Versant HCV RNA 3.0偵測。DNA 製備乃從病人抽取血液以QIAamp DNA blood kit (Qiagen) 萃取DNA,利用PCR Sequence-specific primer typing的技術,細胞中的DNA以特殊序列之引子(Primer)進行PCR增數。若細胞中之DNA含與引子序列互補之序列.則會經PCR而複製,電泳會出現Band。在codon 10其基因型分別為T/T、T/C、C/C,在codon 25其基因型分別為G/G、G/C、C/C。
全部病患中,136位慢性C型肝炎病患接受IFN-�� 6百萬單位皮下注射,每週三次,治療 24週,ribavirin每天口服1000~1200mg,並在治療滿24週之後接受持續六個月以上之追蹤,方完成此一療程。在治療及追蹤期當中,每位病人均常規檢驗血清ALT值(每個月至少一次)及血清HCV RNA(定性RT-PCR,每三個月至少一次)。
病人對IFN-��/ribavirin合併治療之反應定義如下
1) 持續性反應者(sustained responder)
當病人為治療終點反應者,且持續追蹤血清ALT正常,血清HCV RNA呈PCR陰性滿6個月以上,則視為持續性反應者。
2) 非持續性反應者(non-sustained responder)
不具持續性反應之病患
結果發現:
1. TGF-b1基因多形性的codon 10及25其allele、基因型及表現型均與性別、年齡、治療前C型肝炎病毒濃度及血中ALT、AST濃度無關
2. TGF-b1基因多形性在codon 10基因型為T/T則明顯有較高比率感染C型肝炎病毒基因1b型
3. 並無發現任何基因型或表現型與肝臟纖維化或肝臟組織壞死發炎性有明顯相關性。TGF-b1基因多形性在codon 25的分布與肝纖維化傾向在高加索民族有明顯的相關性,但由於在台灣codon 25幾乎百分百為G/G型所以無法進一步分析研究
4. TGF-b1基因多形性在codon 10基因若為T/T型,對干擾素/ribavirin合併治療有較低的持續反應率,乃因T/T型有較高比率感染C型肝炎病毒基因型1b有關
Transforming growth factor-��1 (TGF–��1), which contributes to the activation of hepatic stellate cells(HSC) and their production of extracellular matrix proteins, may promote hepatic fibrogenesis in chronic hepatitis C. The production of TGF-β1 is predominantly under genetic control and significantly associated with gene polymorphism. Two of TGF-β1 genetic polymorphisms have been described in the leader sequence at position +29(codon 10: leucine/proline) and +74(codon 25: arginine /proline) and appears to be associated with hepatic fibrogenesis and to affect the response to antiviral therapy.
This study is to determine the frequency of genotypes associated with TGF- ��1 genetic polymorphisms and investigate their association with HCV genotype, viral load, the severity of liver inflammation, and the response to interferon with ribavirin combination therapy in patients with chronic hepatitis C.
One hundred and forty-five patients with chronic hepatitis C were enrolled in the study. These included 90 males and 55 females, aged between 20 and 73 years (mean 47.1�b11.3 years). Second-generation HCV antibody and hepatitis B surface antigen were detected with commercially available enzyme-linked immunosorbent assay kits. All were positive for anti-HCV antibodies and serum HCV RNA, and negative for hepatitis B surface antigen. Liver histology, assessed blindly by 2 pathologists showed chronic hepatitis of different severity in 131 patients and cirrhosis in 14. Disease activity grade and fibrosis stage were quantitatively scored according to the histological activity index (HAI). Detection of serum HCV RNA was performed using a standardized automated qualitative reverse transcription polymerase chain reaction assay. HCV genotypes 1a, 1b, 2a, 2b and 3a were determined by amplification of the core region using genotype-specific primers described by Okamoto et al. Sixty-five patients were infected by HCV type 1b,43 by type 2a, 17 by type 2b, 5 by mixed types, and 15 had an indeterminate HCV type. Serum HCV RNA levels were measured and performed strictly in accordance with the manufacturer’s instructions. Genomic DNA was purified from whole blood using the QIAamp DNA blood kit according to the manufacturer’s instructions. In PCR sequence-specific primer(SSP) typing , oligonucleotide primers are designed to obtain amplification of specific alleles or groups of alleles. Assignment of alleles is then based on the presence or absence of amplified product usually detected by agarose gel electrophoresis and transillumination. Interpretation of PCR results was based on the presence of the internal control band together with the presence or absence of specific amplified fragment. The genotyping pattern were determined T/T, T/C and C/C at codon 10 and, and G/G , G/C and C/C at codon 25. 136 of all patients were treated 24 weeks with IFN-* at a dose of 6 million units , thrice weekly , combined with 1000-1200 mg of ribavirin, per day. The presence of HCV RNA in the serum was assessed every three months. Sustained viral response was defined as clearance of serum HCV RNA at the end of the therapy and 6 months after the cessation of therapy. All other patients were classified as non-responders.
Our results showed that:
1. All of the alleles, genotypes or phenotypes of TGF-��1 gene polymorphisms at codon 10 and 25 did not correlate to age, sex , pretreatment HCV viral loads, and serum levels of aminotransferase.
2. Patients with the T/T genotype at codon 10 had higher chronic infection rate of HCV genotype 1b
3. No correlation was found between genotypes or phenotypes of TGF-��1 gene polymorphisms and hepatic fibrosis or necroinflammatory activity. Polymorphisms at codon 25 may be associated with hepatic fibrosis in Caucasian populations, but the polymorphism is unlikely to be associated with hepatic fibrosis in Taiwanese population.
4. Lower sustained response rate to combined IFN-* and ribavirin therapy in patients with the T/T genotype at codon 10 was associated with higher infection rate of HCV genotype 1b
摘要……………………………………01
英文摘要………………………………04
前言……………………………………08
材料及方法……………………………10
結果……………………………………15
討論……………………………………18
結論……………………………………22
表格……………………………………24
參考文獻………………………………31
1.Alter MJ, Margolis HS, Krawczynski K, Judson FN, Mares A, Alexander WJ, Hu PY, Miller JK, Gerber MA, Sampliner RE, et al.: The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team. N Engl J Med 1992;327:1899-1905.
2.Gonzalez-Peralta RP, Davis GL, Lau JY: Pathogenetic mechanisms of hepatocellular damage in chronic hepatitis C virus infection. J Hepatol 1994;21:255-259.
3.Border WA, Noble NA: Transforming growth factor beta in tissue fibrosis. N Engl J Med 1994;331:1286-1292.
4.Bedossa P, Paradis V: Transforming growth factor-beta (TGF-beta): a key-role in liver fibrogenesis. J Hepatol 1995;22:37-42.
5.Tilg H, Wilmer A, Vogel W, Herold M, Nolchen B, Judmaier G, Huber C: Serum levels of cytokines in chronic liver diseases. Gastroenterology 1992;103:264-274.
6.Shirai Y, Kawata S, Tamura S, Ito N, Tsushima H, Takaishi K, Kiso S, Matsuzawa Y: Plasma transforming growth factor-beta 1 in patients with hepatocellular carcinoma. Comparison with chronic liver diseases. Cancer 1994;73:2275-2279.
7.Tsushima H, Kawata S, Tamura S, Ito N, Shirai Y, Kiso S, Doi Y, Yamada A, Oshikawa O, Matsuzawa Y: Reduced plasma transforming growth factor-beta1 levels in patients with chronic hepatitis C after interferon-alpha therapy: association with regression of hepatic fibrosis. J Hepatol 1999;30:1-7.
8.Powell EE, Edwards-Smith CJ, Hay JL, Clouston AD, Crawford DH, Shorthouse C, Purdie DM, Jonsson JR: Host genetic factors influence disease progression in chronic hepatitis C. Hepatology 2000;31:828-833.
9.Kanzler S, Baumann M, Schirmacher P, Dries V, Bayer E, Gerken G, Dienes HP, Lohse AW: Prediction of progressive liver fibrosis in hepatitis C infection by serum and tissue levels of transforming growth factor-beta. J Viral Hepat 2001;8:430-437.
10.Fujii D, Brissenden JE, Derynck R, Francke U: Transforming growth factor beta gene maps to human chromosome 19 long arm and to mouse chromosome 7. Somat Cell Mol Genet 1986;12:281-288.
11.Cambien F, Ricard S, Troesch A, Mallet C, Generenaz L, Evans A, Arveiler D, Luc G, Ruidavets JB, Poirier O: Polymorphisms of the transforming growth factor-beta 1 gene in relation to myocardial infarction and blood pressure. The Etude Cas-Temoin de l''Infarctus du Myocarde (ECTIM) Study. Hypertension 1996;28:881-887.
12.Awad MR, El-Gamel A, Hasleton P, Turner DM, Sinnott PJ, Hutchinson IV: Genotypic variation in the transforming growth factor-beta1 gene: association with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. Transplantation 1998;66:1014-1020.
13.Grainger DJ, Heathcote K, Chiano M, Snieder H, Kemp PR, Metcalfe JC, Carter ND, Spector TD: Genetic control of the circulating concentration of transforming growth factor type beta1. Hum Mol Genet 1999;8:93-97.
14.Perrey C, Pravica V, Sinnott PJ, Hutchinson IV: Genotyping for polymorphisms in interferon-gamma, interleukin-10, transforming growth factor-beta 1 and tumour necrosis factor-alpha genes: a technical report. Transpl Immunol 1998;6:193-197.
15.McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZD, Ling MH, Cort S, Albrecht JK: Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 1998;339:1485-1492.
16.Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, Bain V, Heathcote J, Zeuzem S, Trepo C, Albrecht J: Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 1998;352:1426-1432.
17.Castilla A, Prieto J, Fausto N: Transforming growth factors beta 1 and alpha in chronic liver disease. Effects of interferon alfa therapy. N Engl J Med 1991;324:933-940.
18.Roulot D, Durand H, Coste T, Rautureau J, Strosberg AD, Benarous R, Marullo S: Quantitative analysis of transforming growth factor beta 1 messenger RNA in the liver of patients with chronic hepatitis C: absence of correlation between high levels and severity of disease. Hepatology 1995;21:298-304.
19.Vidigal PG, Germer JJ, Zein NN: Polymorphisms in the interleukin-10, tumor necrosis factor-alpha, and transforming growth factor-beta1 genes in chronic hepatitis C patients treated with interferon and ribavirin. J Hepatol 2002;36:271-277.
20.Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, Kiernan TW, Wollman J: Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981;1:431-435.
21.Yu ML, Chuang WL, Chen SC, Lin ZY, Hsieh MY, Wang LY, Chang WY: Clinical application of the Quantiplex HCV RNA 2.0 and Amplicor HCV Monitor assays for quantifying serum hepatitis C virus RNA. J Clin Pathol 1999;52:807-811.
22.Dai CY, Yu ML, Chuang WL, Hou NJ, Hou C, Chen SC, Lin ZY, Hsieh MY, Wang LY, Chang WY: The response of hepatitis C virus and TT virus to high dose and long duration interferon-alpha therapy in naive chronic hepatitis C patients. Antiviral Res 2002;53:9-18.
23.Hoffmann SC, Stanley EM, Cox ED, DiMercurio BS, Koziol DE, Harlan DM, Kirk AD, Blair PJ: Ethnicity greatly influences cytokine gene polymorphism distribution. Am J Transplant 2002;2:560-567.
24.Suzuki S, Tanaka Y, Orito E, Sugauchi F, Hasegawa I, Sakurai M, Fujiwara K, Ohno T, Ueda R, Mizokami M: Transforming growth factor-beta-1 genetic polymorphism in Japanese patients with chronic hepatitis C virus infection. J Gastroenterol Hepatol 2003;18:1139-1143.
25.Lu LY, Cheng HH, Sung PK, Yeh JJ, Shiue YL, Chen A: Single-nucleotide polymorphisms of transforming growth factor-beta1 gene in Taiwanese patients with systemic lupus erythematosus. J Microbiol Immunol Infect 2004;37:145-152.
26.Lee JG, Ahn C, Yoon SC, Park JH, Eo HS, No JJ, Kim KH, Lee EJ, Hwang YH, Hwang DY, Kim YS, Han JS, Kim S, Lee JS, Kim SH: No association of the TGF-beta1 gene polymorphisms with the renal progression in autosomal dominant polycystic kidney disease (ADPKD) patients. Clin Nephrol 2003;59:10-16.
27.Ohtsuka T, Yamakage A, Yamazaki S: The polymorphism of transforming growth factor-beta1 gene in Japanese patients with systemic sclerosis. Br J Dermatol 2002;147:458-463.
28.Yoshioka K, Kakumu S, Wakita T, Ishikawa T, Itoh Y, Takayanagi M, Higashi Y, Shibata M, Morishima T: Detection of hepatitis C virus by polymerase chain reaction and response to interferon-alpha therapy: relationship to genotypes of hepatitis C virus. Hepatology 1992;16:293-299.
29.Chen CH, Sheu JC, Wang JT, Huang GT, Yang PM, Lee HS, Lee CZ, Chen DS: Genotypes of hepatitis C virus in chronic liver disease in Taiwan. J Med Virol 1994;44:234-236.
30.Yu ML, Chuang WL, Lu SN, Chen SC, Wang JH, Lin ZY, Hsieh MY, Wang LY, Chang WY: The genotypes of hepatitis C virus in patients with chronic hepatitis C virus infection in southern Taiwan. Kaohsiung J Med Sci 1996;12:605-612.
31.Amoroso P, Rapicetta M, Tosti ME, Mele A, Spada E, Buonocore S, Lettieri G, Pierri P, Chionne P, Ciccaglione AR, Sagliocca L: Correlation between virus genotype and chronicity rate in acute hepatitis C. J Hepatol 1998;28:939-944.
32.Barrett S, Collins M, Kenny C, Ryan E, Keane CO, Crowe J: Polymorphisms in tumour necrosis factor-alpha, transforming growth factor-beta, interleukin-10, interleukin-6, interferon-gamma, and outcome of hepatitis C virus infection. J Med Virol 2003;71:212-218.
33.Gewaltig J, Mangasser-Stephan K, Gartung C, Biesterfeld S, Gressner AM: Association of polymorphisms of the transforming growth factor-beta1 gene with the rate of progression of HCV-induced liver fibrosis. Clin Chim Acta 2002;316:83-94.
34.Tag CG, Mengsteab S, Hellerbrand C, Lammert F, Gressner AM, Weiskirchen R: Analysis of the transforming growth factor-beta1 (TGF-beta1) codon 25 gene polymorphism by LightCycler-analysis in patients with chronic hepatitis C infection. Cytokine 2003;24:173-181.
35.Lauer GM, Walker BD: Hepatitis C virus infection. N Engl J Med 2001;345:41-52.
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關論文
 
1. 8. 徐麗萍(1993),「期貨市場管理體系規劃之介紹」,證券管理雜誌,第十一卷第二期,頁31-33
2. 8. 徐麗萍(1993),「期貨市場管理體系規劃之介紹」,證券管理雜誌,第十一卷第二期,頁31-33
3. 2. 古永嘉、吳世勛(1995),「以DEA模式評估我國商業銀行之經營效率」,管理與系統,第二卷第二期,頁145-165。
4. 2. 古永嘉、吳世勛(1995),「以DEA模式評估我國商業銀行之經營效率」,管理與系統,第二卷第二期,頁145-165。
5. 1. 王國樑、翁志強、張美玲(1998),「台灣綜合券商技術效率之探討」,證券市場發展季刊,第十卷第二期,頁93-115。
6. 1. 王國樑、翁志強、張美玲(1998),「台灣綜合券商技術效率之探討」,證券市場發展季刊,第十卷第二期,頁93-115。
7. 9. 馬裕豐(1994),「銀行分支單位經營績效衡量模式之建構---資料包絡分析模式(DEA)的應用」,企銀季刊,第十八卷第一期,頁102-121;第二期,頁13-24。
8. 9. 馬裕豐(1994),「銀行分支單位經營績效衡量模式之建構---資料包絡分析模式(DEA)的應用」,企銀季刊,第十八卷第一期,頁102-121;第二期,頁13-24。
9. 14. 葉桂珍、陳昱志(1995),「銀行經營績效分析-資料包絡分析法(DEA)與財務比率法之比較」,企銀季刊,第十九卷第二期,頁30-39。
10. 14. 葉桂珍、陳昱志(1995),「銀行經營績效分析-資料包絡分析法(DEA)與財務比率法之比較」,企銀季刊,第十九卷第二期,頁30-39。
11. 18. 蔡櫻瑜(2003),「期貨商自有資金運用及業務範圍相關規定之介紹」,證券暨期貨管理雜誌,第二十一卷第三期,頁39-48
12. 18. 蔡櫻瑜(2003),「期貨商自有資金運用及業務範圍相關規定之介紹」,證券暨期貨管理雜誌,第二十一卷第三期,頁39-48