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研究生:周怡均
研究生(外文):Yi-Chun Chou
論文名稱:B型肝炎病毒基因CorePromoter和Precore區域之變異和肝細胞癌的關係:重疊病例對照研究
論文名稱(外文):Genetic Variation in Core Promoter and Precore of Hepatits B Virus and Hepatocellular Carcinoma: A Nested Case-Control Study
指導教授:于明暉于明暉引用關係
指導教授(外文):Ming-Whei Yu
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:流行病學研究所
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:2004
畢業學年度:92
語文別:中文
論文頁數:34
中文關鍵詞:Precore 區域Core Promoter肝細胞癌B型肝炎病毒
外文關鍵詞:Hepatits B VirusCore PromoterPrecoreHepatocellular Carcinoma
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背景:有關B型肝炎病毒 (hepatitis B virus; HBV)基因core promoter (CP)和precore (PC)區域變異和慢性肝臟疾病或肝細胞癌 (HCC)的研究上相當稀少。本研究目的在於分析HBV基因CP和PC區域 (nt1685~nt1900)各核甘酸位置變異和HCC發生的關係,並探討HBV基因型及DNA濃度和CP/PC序列變異間的關係。

方法:利用重疊病例對照研究設計,研究個案來自一個1988-1992年間收案的男性HBV帶原者世代,共有124名病例和159名對照個案。病例和對照個案在進入研究年齡及血液樣本採集時間個別匹配。除了利用研究對象進入研究所採集的血液進行分析,同時在追蹤期間進行第二個時點分析,病例第二個時點的分析是選擇在病例發病兩年以內,對照個案分析時點係參照病例第二時點,選擇與其距離最近的時間。共有79名病例和92名對照納入第二時點分析。

結果:以基線血液檢體進行分析,發現有11個核甘酸位置的變異和HCC顯著相關,其中1762T/1764A雙突變和1896G的變異和HCC的adjusted OR分別為3.15 (95%CI=1.83-5.41) 和1.78 (95%CI=1.05-2.99)。另外還包括CP上1703G、1719T、1726A、1727A/G、1730C、1753C、1799C以及PC上1862G,各點的adjusted OR約介於2~5倍間。HCC危險性隨變異點累積數顯著上升 (趨勢檢定, P<0.0001)。由分析基線和追蹤期間之血液檢體,發現在兩時點穩定呈現變異型態的狀況顯著增加HCC危險性,而僅在任一時點測得變異型態,均和HCC無顯著相關。PC區域變異和基因型無關,CP區域各點變異均是C基因型者顯著高於其他基因型者。但各核甘酸位置的變異對HBV DNA濃度的影響卻不顯著。依HBV基因型C或非C進行分層分析,未發現個變異點和HCC的關係隨基因型改變。

結論:HBV基因CP/PC區域各個核甘酸位置和HCC發展具有顯著相關。CP區域變異和基因型有關但對HCC危險性亦有其獨立作用。但大部份的核甘酸變異,除了1896G外,並不影響HBV病毒濃度的表現。
Background: The aim of this study was to investigate the association between variation in the core promoter (CP) and precore (PC) regions of HBV genome and HCC. We also assessed the associations of the genetic variants of HBV with genotype and plasma DNA levels.

Methods: A nested case-control study involving a total of 124 cases and 159 controls derived from a cohort of 4841 male HBV carriers was conducted. For cases, both blood samples drawn at baseline and collected during follow-up within two years before the time of cancer diagnosis were used for analysis of viral factors. Controls were matched to cases by year of birth and the times of blood drawn. The second time-point analysis included 79 cases and 92 controls.

Results: At baseline, a total of 11 genetic variants were associated with HCC, giving adjusted ORs of from 2~5. The ORs of HCC associated with haboring 1762T/1764A double mutation and 1896G were 3.15 (95%CI=1.84-5.41) and 1.78 (95%CI=1.05-2.99), respectively. The risk of HCC increased with increacing number of genetic variants of HBV (test for trend, P<0.0001). For most of the study subjects, the HBV genetic variation was the same in the base-line samples and in the samples collected at follow-up. The OR of HCC for each genetic variant was increased among subjects persistently harboring “variant type”. Genetic variation in the PC region was not associated with HBV genotype, but variation in the CP region was more prevalent in subjects with C genotype than in those with non-C genotype. After adjusting potential confounders including age and genotype, all the genetic variants were not significantly associated with HBV viral load, except 1896G. We did not find evidence for a modification effect of genotype on the association between genetic variants in the CP/PC regions of HBV and HCC.

Conclusion: Genetic variants in the CP/PC region of HBV were associated with the development of HCC. HBV genotype was associated with variation in CP but not PC. Most variants (except 1896G) appeared not to affect the replication activity of HBV.
目錄
前言………………………………………………………………………1
材料與方法………………………………………………………………5
研究世代………………………………………………………………5
病例和對照組…………………………………………………………6
實驗分析………………………………………………………………6
統計方法………………………………………………………………8
結果………………………………………………………………………9
病例組和對照組的基本資料…………………………………………9
CP/PC區域核甘酸變異和HCC危險性…………………………………9
追蹤期間HBV基因CP/PC區域核甘酸變異和HCC危險性……………10
HBV CP/PC基因變異和基因型、HBV DNA濃度間的關係…………11
討論……………………………………………………………………12
參考文獻………………………………………………………………18

圖表目錄
圖一 病例組和對照組在HBV基因序列nt1685~nt1900各點變異頻率之差異…………………………………………………………………24
表一 病例組和對照組的基線資料特徵……………………………25
表二 HBV CP/PC區域變異與HCC的關係……………………………26
表三 HBV CP/PC區域變異累積數目和HCC的關係…………………28
表四 HBV CP/PC區域累積變異型態和HCC的關係…………………29
表五 追蹤期間HBV基因CP/PC區域變異和HCC之間的關係……….30
表六 病例和對照組CP/PC區域核甘酸變異和病毒基因型之間的關係:以基線血液檢體分析結果………………………………………32
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