臺灣博碩士論文加值系統

一、 人類白血球抗原三端非轉譯區變異與B型肝炎進展之相關性研究
背景及研究目的：慢性B型肝炎患者的病程進展具有很高的變異性，而其影響因子迄今未明。以往的全基因組研究顯示，HLA-DP基因之變異和慢性B型肝炎有顯著之相關性。本研究的目的在探討HLA 3’UTR區域之變異與慢性B型肝炎進程之相關性。研究方法：本研究在初探階段利用次世代定序針對1174位慢性B型肝炎帶原者的HLA基因3’UTR區域之遺傳變異進行基因定型，並以邏輯迴歸分析計算勝算比(OR)及其95%信賴區間(95% CI)。結果：HLA-DQA1 rs9282076基因型與 HBeAg 之血清廓清有顯著相關[C|CA vs. C|C 的勝算比(95% 信賴區間)為0.38 (0.19-0.76)]，而HLA-DPB1 rs934基因型和HBV DNA之血清廓清有顯著相關[非AA之基因型 vs. AA基因型的勝算比(95% 信賴區間)為2.31 (1.14-4.66)]。在HLA-B及HLA-G 3’UTR當中，有多個遺傳變異和HBsAg之血清廓清有顯著相關，並且累加性地提高HBsAg血清廓清之機會。進一步預測分析，其中有許多遺傳變異可能會改變miRNA和HLA mRNA之鍵結，包括HLA-DPB1 (rs934), HLA-G (rs1063320) and HLA-B (rs1055849, rs1058067, rs2770)。結論: HLA 3’UTR區段之遺傳變異可能會影響B型肝炎病毒感染標誌之血清廓清。

二、 黃麴毒素暴露與肝硬化及肝癌風險之相關性研究
背景及研究目的：B型肝炎病毒與黃麴毒素對於肝癌之發生風險具有協同交互作用，但黃麴毒素暴露對於發生肝硬化風險之影響仍不明確。以往黃麴毒素對於C型肝炎患者罹患肝癌風險之相關研究，也非常有限。本研究的目的是利用巢式病例對照研究，探討黃麴毒素暴露對於B型肝炎患者罹患肝硬化及肝癌之風險的影響，以及評估黃麴毒素暴露對於C型肝炎患者罹患肝癌之風險的影響。研究方法：測量肝硬化及肝癌病例組，以及未罹病之對照組，在進入研究時所收集之血清樣本的黃麴毒素(AFB1)-白蛋白鍵結物濃度，並以邏輯迴歸分析勝算比(OR)及其95%信賴區間(95% CI)。結果：慢性B型肝炎患者在追蹤九年內所發生之肝硬化與肝硬化性肝癌，以及追蹤四年內所發生之非肝硬化性肝癌，都和AFB1-白蛋白鍵結物血清濃度呈現顯著之劑量效應關係。高血清濃度者相較於血清未測出AFB1-白蛋白鍵結物者，有顯著偏高之肝硬化、肝硬化性肝癌及非肝硬化性肝癌風險，其勝算比(95% 信賴區間)分別為2.45 (1.51-3.98)、5.47 (2.20-13.63)及5.39 (1.11-26.18)；而在罹患肝硬化之B型肝炎患者當中，產生肝癌之風險仍與AFB1-白蛋白鍵結物血清濃度有顯著之劑量效應關係，高血清濃度者相較於血清未測出AFB1-白蛋白鍵結物者，罹患肝癌之風險勝算比(95% 信賴區間)為3.04 (1.11-8.30)。C型肝炎病毒抗體陽性個案在追蹤八年內，AFB1-白蛋白鍵結物血清濃度偏高者罹患肝癌之風險，相較於血清未測出AFB1-白蛋白鍵結物者，其勝算比 (95% 信賴區間)為3.37 (1.39-8.14)。在20年長期追蹤期間，AFB1-白蛋白鍵結物血清濃度偏高者發生肝硬化、病毒性肝癌或非病毒性肝癌之時間，均顯著早於AFB1-白蛋白鍵結物未測得或濃度偏低者。結論：黃麴毒素之暴露會增加B型肝炎所致之肝硬化、肝癌以及C型肝炎所致之肝癌風險。

I. Association study of genetic variants of human leukocyte antigen 3'UTRs with the outcomes of chronic hepatitis B virus infection
Background and aims: The disease spectrum of chronic hepatitis B virus (HBV) infection is highly variable and the contributing factors remain largely unknown. HLA-DP variants showed the strongest genome-wide association with chronic hepatitis B. This study aims to identify the HLA 3’UTR variants associated with the seroclearance of HBV viral markers and cirrhosis and hepatocellular carcinoma (HCC). Genetic variants in the 3’ untranslated regions (3’UTRs) of HLA genes were genotyped using next generation sequencing in 1174 chronic HBV carriers in the discovery stage. Logistic regression was performed to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs). Results: HLA-DQA1 variant rs9282076 was associated HBeAg seroclearance [C|CA vs. C|C, adjusted OR (95% CI), 0.38 (0.19-0.76)]. HLA-DPB1 rs934 was significantly associated with seroclearance of HBV DNA with the adjusted ORs (95% CIs) of 2.31 (1.14-4.66) for non-AA genotype compared to AA genotype. Several variants in HLA-B and HLA-G were significantly and cumulatively associated with increased risk of HBsAg seroclearance. In silico analysis predicted that these variants associated with seroclearance of HBV markers can potentially alter the miRNA binding to the 3’UTR of HLA-DPB1 (rs934), HLA-G (rs1063320) and HLA-B (rs1055849, rs1058067, rs2770). Conclusion: Genetic variants of HLA 3’UTR regions may contribute to the heterogeneity in seroclearance of HBV markers in chronic HBV carriers.

II. Association study of aflatoxin B1 exposure with the risk of cirrhosis and HCC
Background and aims: Synergistic interaction between aflatoxin B1 (AFB1) and HBV infection on HCC risk is well-documented. However, the relation between AFB1 and cirrhosis remains inconclusive. Besides, studies of AFB1-associated HCC risk with respect to hepatitis C virus (HCV) infection showed contradictory results. This case-control study nested in a large community-based cohort aims to assess the effect of AFB1 exposure on cirrhosis and HCC in chronic HBV carriers and to investigate effect of AFB1 exposure on HCC in relation to HCV infection. Methods: Baseline serum AFB1-albumin adduct levels were measured in 232 cirrhosis cases, 262 HCC cases and 577 controls in chronic HBV carriers and also 100 HCC cases and 1767 controls of anti-HCV seronegative participants and 131 HCC cases and 230 controls of anti-HCV seropositive participants. Multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression. Results: Among chronic HBV carriers, there were significant dose-response relations with baseline serum AFB1-albumin adduct level for cirrhosis and cirrhotic HCC within 9 years after entry as well as non-cirrhotic HCC within 4 years after entry. The aORs (95% CIs) for high vs. undetectable serum AFB1-albumin adduct levels were 2.45 (1.51-3.98) for cirrhosis, 5.47 (2.20-13.63) for cirrhotic HCC, and 5.39 (1.11-26.18) for non-cirrhotic HCC, respectively. There remained a significant dose-response relation between serum AFB1-albumin adduct level and HCC risk in cirrhosis patients, showing an aOR (95% CI) of 3.04 (1.11-8.30) for high vs. undetectable serum levels. On the other hand, elevated AFB1-albumin adduct levels were associated with higher risk of HCC developed within 8 years of follow-up in anti-HCV seropositive subjects. The adjusted OR (95% CI) was 3.37 (1.39-8.14) for high vs. undetectable serum levels. In addition, within 20 years of follow-up, the onset time of HBV-related cirrhosis and HCC resulting from both viral and non-viral etiology were significantly shorter in participants with high serum levels of AFB1-albumin adducts than those with low/undetectable levels. Conclusion: AFB1 exposure may increase the risk of HBV-related cirrhosis and HCC and also the risk of HCV-related HCC.

Table of Contents
致謝……i
摘要……ii
Abstract……iv
Table of Contents……vi
List of Figures……x
List of Tables……xi
Chapter 1. Introduction……1
1.1 Viral hepatitis……1
1.2 Hepatitis B……1
1.3 Hepatitis B virus……2
1.4 Hepatitis C……2
1.5 Hepatitis C virus……3
1.6 Study aim……3
Chapter 2. Association study of genetic variants of human leukocyte antigen 3'UTRs with the outcomes of chronic hepatitis B virus infection……4
2.1 Introduction……4
2.1.2 Natural history of chronic hepatitis B……4
2.1.3 Immunopathogenesis of HBV infection……5
2.1.4 Risk factors associated with the outcomes of chronic hepatitis B……11
2.1.5 Human leukocyte antigens (HLAs)……12
2.1.6 Association between HLAs and chronic hepatitis B outcomes……13
2.1.7 Knowledge gap……15
2.1.8 Specific aims……17
2.2 Materials and methods……18
2.2.1 Study population……18
2.2.2 Data collection, serological testing and follow-up for liver cirrhosis and hepatocellular carcinoma……18
2.2.3 Study design of the discovery cohort……20
2.2.3.1 Matched case-control studies in the eligible cohort……20
2.2.3.2 Subject selection of the discovery cohort……22
2.2.4 Sequencing and genotyping of HLA 3’UTR regions……23
2.2.5 Statistical analysis……27
2.2.6 Prediction of putative miRNA-related SNPs……27
2.3 Results……28
2.3.1 Sequencing quality……28
2.3.2 Reproducibility……28
2.3.3 Prevalent HLA 3’ UTR variants……28
2.3.4 Association analysis of HLA 3’UTR variants for the disease outcomes of chronic hepatitis B in the discovery stage……29
2.3.4.1 HBeAg seroclearance……29
2.3.4.2 HBV DNA seroclearance……30
2.3.4.3 HBsAg seroclearance……30
2.3.4.4 Cirrhosis……32
2.3.4.5 Hepatocellular carcinoma……32
2.3.5 Potential impact of identified variants on the miRNA-target interaction……32
2.4 Discussion……33
Tables……41
Figures……70
Appendix……77
Chapter 3. Association study of aflatoxin B1 exposure with the risk of cirrhosis and HCC……87
3.1 Introduction……87
3.1.1 Liver cirrhosis and hepatocellular carcinoma……87
3.1.2 Aflatoxin……88
3.1.3 Epidemiology studies of aflatoxin exposure and HCC risk……90
3.1.4 Epidemiology studies of aflatoxin exposure and cirrhosis risk……93
3.1.5 Knowledge gap……94
3.1.6 Specific aims……95
3.2 Materials and methods……96
3.2.1 Study population……96
3.2.2 Study subjects……96
3.2.3 Data collection and serological testing……97
3.2.4 Follow-up for liver cirrhosis and hepatocellular carcinoma……98
3.2.5 Measurement of serum AFB1-albumin adduct levels……98
3.2.6 Statistical analysis……99
3.3 Results……101
3.3.1 AFB1 exposure and HCC onset in chronic HBV carriers……101
3.3.2 AFB1 exposure and the onset of cirrhosis, cirrhotic HCC and non-cirrhotic HCC in chronic HBV carriers……101
3.3.3 Time-dependent association between AFB1 exposure and the risk of cirrhosis and HCC in chronic HBV carriers……102
3.3.4 Effect of AFB1 exposure on risk of cirrhosis and HCC in chronic HBV carriers within 9 years of follow-up……103
3.3.5 AFB1 exposure and HCC onset in HCV-uninfected and HCV-infected participants……105
3.3.6 Time-dependent association between AFB1 exposure and HCC risk……105
3.3.7 Predictors of HCC within 8 years of follow-up……106
3.3.8 Effect of AFB1 exposure on risk of HCC in HCV-uninfected participants within 8 years of follow-up……107
3.3.9 Effect of AFB1 exposure on risk of HCC in HCV-infected participants within 8 years of follow-up……107
3.4 Discussion……109
Tables……116
Figures……131
Chapter 4. Conclusion and future perspectives……134
References……136

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