Interferon gamma訊號路徑上之基因變異與B型肝炎病毒複製活性關係

Abstract

背景：有關影響HBV DNA複製活性遺傳因子，尚相當缺乏研究。本研究利用家族相關性研究與族群長期追蹤研究，探討在IFNG訊號路徑中之基因上是否存有一個至多個基因多型性（SNP）變異與HBV DNA濃度相關。 材料與方法：家族資料為包括HCC指標個案家族269家共729名B肝帶原者。長期追蹤資料包括756名男性B肝帶原者，其中共493人HBV DNA濃度持續高（至少連續四年所測HBV DNA濃度≧4.39 log10(copies/ml)）；263人HBV DNA濃度持續低（至少連續四年所測HBV DNA濃度＜4.39 log10(copies/ml)）。血漿中HBV DNA之測量採以TaqMan方法為基礎的real time PCR進行定量。家族資料分析是以傳遞不平衡檢定原理，分別採用FBAT與QTDT方法分析。長期追蹤分析則以廣義線性混合模型估計各SNP標記對16年期間多時點之HBV DNA濃度變動的影響。 結果：IFNGR2基因上共三個SNP標記，在家族研究與長期追蹤研究中皆發現與HBV DNA濃度呈現顯著相關，且考慮FDR估計值後其q value皆小於0.02。另外在STAT1基因上，則於家族資料或長期追蹤研究中共發現四個SNP標記與HBV DNA濃度呈現顯著相關，且經FDR計算後，q value介於0.015到0.36之間。進一步在基因區域進行半套型與HBV DNA濃度相關性分析，於IFNGR2基因與STAT1基因上皆發現具有危險性之半套型。 結論：藉由家族及族群長期追蹤兩種研究方式共同驗證，於IFNGR2基因與STAT1基因上皆發現存有基因多型性變異與HBV DNA濃度相關。未來值得更進一步進行基因定序方式或基因功能性研究加以證實。

Background: The role of host genetic factors in hepatitis B virus (HBV) replication activity remains largely unknown. We used both family-based association study and an independent set of unrelated subjects recruited from a longitudinal cohort study to investigate the association between single nucleotide polymorphisms (SNPs) in interferon gamma (IFNG) signaling pathway and circulating HBV DNA levels. Materials and Methods: Family-based study consisted of 729 HBV carriers from 269 families ascertained through a single HCC index patient. The longitudinal cohort study contained two groups: 1) 493 HBV carriers who had persistently high HBV DNA levels (defined as having a HBV DNA level≥ 4.39 log10 (copies/ml) for ≥4 years), and 2) 263 HBV carriers who had persistently low HBV DNA levels (defined as having a HBV DNA level< 4.39 log10 (copies/ml) for ≥4 years). A TaqMan assay was used to determine HBV DNA in plasma. We performed FBAT and QTDT for family-based association analysis, applied generalized linear mixed model to estimate the effect of at-risk genotypes on the change of plasma HBV DNA with time during up to 16 years of follow-up in unrelated subjects. Result: We found three significant SNPs in the IFNGR2 gene, with a false-discovery rate q value of <0.02. These associations were consistently observed in the family-based study and longitudinal study. In the STAT1 gene, four SNPs showed association with HBV DNA either in the family-based study or in the longitudinal study. The false-discovery rate q values for these associations range from 0.015 to 0.36. Further haplotype analysis discovered at-risk haplotypes in the STAT1 gene and IFNGR2 gene. Conclusions: Both our family-based association study and longitudinal cohort study on unrelated individuals suggest that genetic variation in the IFNGR2 and STAT1 genes may play some role in the HBV replication activity. Further studies on re-sequencing the entire gene region or identification of the functions on SNPs are warranted.