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標題: | 搜尋HLA區域肝細胞癌家族控制B型肝炎病毒複製活性之數量性狀基因座 Searching for a Quantitative Trait Locus in HLA Region for Host Control of HBV Replication in Families with Hepatocellular Carcinoma |
作者: | Shih-Yun Chou 周世韻 |
指導教授: | 于明暉(Ming-Whei Yu) |
關鍵字: | B型肝炎病毒,病毒量,HLA,家族相關性分析,傳遞不平衡檢定,拷貝數變異,重疊病例對照研究, Hepatitis B virus,viral load,HLA,family-based association study,QTDT,CNV,nested case-control study, |
出版年 : | 2009 |
學位: | 碩士 |
摘要: | 背景:血液中B型肝炎病毒DNA濃度稱為B型肝炎病毒量,不僅可以反應病毒在體內的複製活性,也是肝細胞癌的重要危險因子。此外,染色體6p21.3區域除包含人類白血球抗原(HLA)基因外,亦有許多和病毒感染有關的免疫基因;本研究目的為在6p21.3位置尋找與病毒量控制相關之數量性狀基因座(QTL)。材料與方法:本研究第一階段採家族相關性分析,藉由收集HCC指標個案之親屬,共有309個家族及846位B肝帶原者(474位男性及372位女性),以傳遞不平衡原理,採用QTDT分析6p21.3區域上14個微衛星標記(microsatellite marker)。根據QTDT結果,我們在長期追蹤樣本中選取115名HCC病例及345名年齡配對之對照,採重疊病例對照研究法分析此區域之DNA拷貝數的變異(copy number polymorphism)對HBV病毒量控制及HCC發生影響。結果:4個DNA標記(D6S273, D6S1629, D6S1202i and D6S1611i)在QTDT分析結果中和病毒量呈現顯著相關,最顯著的結果出現在D6S1629(P=0.0006; permutated P=0.0010),此標記在多重比較校正後依然呈現顯著結果(p=0.05)。下一階段CNP分析也有相同結果,分析之CNP距離D6S1629約130kb,在家族研究及重疊病例對照研究中均和病毒量呈現顯著負相關。此外,此CNP也和肝硬化(1 vs 2 copies: 相對危險性=3.05; 95%信賴區間=1.46-6.37)及肝癌(1 vs 2 copies: 相對危險性=3.22; 95%信賴區間=1.63-6.35)發生有顯著危險性。結論:此一包含CNP之HLA區域可能和宿主HBV控制及HCC發展有關,CNP相關功能性分析值得進一步研究。 Background: Hepatitis B virus (HBV) load measured in terms of HBV DNA levels in blood is an index of viral replication activity and an important risk factor for hepatocellular carcinoma (HCC). Many genes in human leukocyte antigen (HLA) region encode proteins critical in activating immune response to viral infection. This study aimed to localize quantitative trait loci for host control of HBV viral load in this region. Materials and Methods: The family sample consisted of 846 HBsAg-positive subjects (474 men and 372 women) from 309 different families; each was ascertained through a single HBsAg-positive index patient with HCC. We performed family-based association analysis by using QTDT with a high-density map of genetic markers across a 7.2-Mb region at 6p21.3. To further determine whether HLA alleles may affect HBV viremia and thus the development of HCC, we analyzed a copy number polymorphism (CNP) located near an implicated region identified by QTDT in a case-control sample containing 115 HCC cases and 345 age-matched controls nested within a longitudinal cohort study. Result: Significant associations with HBV viremia were found with QTDT for 4 genetic markers (D6S273, D6S1629, D6S1202i and D6S1611i), with marker D6S1629 showing maximal association (nominal P=0.0006; permutated P=0.0010). The association with marker D6S1629 remained significant even after the most conservative correction for multiple tests by Bonferroni procedure (p=0.05). We consistently observed an inverse association between the number of a CNP, located ~130 kb apart from marker D6S1629, and reduced viral load in both family and nested case-control studies. In addition, copy loss was observed to be a risk factor for the development of liver cirrhosis (one vs two copies: adjusted odds ratio=3.05; 95% confidence interval=1.46-6.37) and HCC (one vs two copies: adjusted odds ratio=3.22; 95% confidence interval=1.63-6.35). Conclusions: The data indicate that a CNV in HLA region may be associated with high viremia of HBV and predisposition to HCC. Further functional studies focusing on the investigation of the nature of this CNV that is underling our observed association are warranted. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/42914 |
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顯示於系所單位: | 流行病學與預防醫學研究所 |
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