B型肝炎病毒核基因上變異和肝細胞癌之關係：縱斷世代研究

Abstract

背景：HBV core 基因所產生的HBcAg，是毒殺性T淋巴球主要的攻擊目標，core基因突變會使得被免疫系統辨識的抗原決定位發生改變，因而逃脫免疫反應。本研究探討HBV core基因上的突變和肝細胞癌(hepatocellular carcinoma；HCC)自然史的關係。 材料與方法：第一階段先利用nested case-control study所獲得定序分析資料找尋和HCC顯著相關之genotype-independent 單點核苷酸變異(single nucleotide polymorphisms；SNP)；第二階段對所找到的SNPs，發展適當的TaqMan probe，在一個追蹤16年的case-cohort study偵測SNPs在長時間的穩定性，及SNPs對病毒因子和疾病狀態的影響。 結果：經過整個core基因的全區域掃描，我們發現五個genotype-independent SNPs對於HCC有保護作用。在基線時，帶有這些SNPs之變異型者，其HBV DNA濃度、HBeAg陽性率皆顯著低於野生型，anti-HBe則相反，而且所帶有的變異型數目和HCC或HBeAg陽性狀態呈直線負相關。在追蹤期間，變異型相對於野生型穩定性較低。具有變異型者其追蹤期間ALT異常和肝硬化的比率皆顯著低於野生型，同時這些變異型和HBV DNA長期變動趨勢具有緊密相關性。 結論：HBV core基因突變和HBeAg陰轉及病毒複製活性有關，並有可能影響後續疾病狀態。

Background & Aims: HBcAg which is encoded by HBV core gene is immunological target of cytotoxic T cell. Genetic variation in the core gene changes the structure of epitope and escapes immune response. We investigated the association between genetic variation in the HBV core gene and natural history of hepatocellular carcinoma (HCC). Materials & Methods: First, we used sequence data from a nested case-control study to identify genotype-independent single nucleotide polymorphisms (SNPs) associated with HCC. At the second stage, we developed novel TaqMan probes for identification of viral SNPs. Then an investigation was performed with a case-cohort study on the longitudinal stability of SNPs and their effects on the change of viral factors and disease progression over 16 years of follow-up. Results: We found five genotype-independent SNPs inversely associated with the risk of HCC through a scan of the whole core gene region. At baseline, harboring mutants of the above SNPs were associated with a lower plasma HBV DNA levels and HBeAg-positive rate but a higher prevalence of anti-HBe positivity. There was an inverse linear relationship for the accumulation of core gene mutants with HCC risk and HBeAg positivity. During follow-up, mutants exhibited a lower stability than wild type. The emergence of mutants was associated with sustained normalization of ALT and decreased risk of cirrhosis. It was tightly correlated with change in HBV DNA over time. Conclusions: Mutation in the HBV core gene may play some role in the HBeAg seroconversion and HBV replication activity, and thus affect disease progression.