乙型肝炎病毒血症：其遗传性及其与干扰素 γ 信号通路常见遗传变异的关联。

Hepatitis B viraemia: its heritability and association with common genetic variation in the interferon gamma signalling pathway.

机构信息

Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Zhongzheng District, Taipei, Taiwan.

出版信息

Gut. 2011 Jan;60(1):99-107. doi: 10.1136/gut.2010.207670. Epub 2010 Oct 27.

DOI:10.1136/gut.2010.207670

PMID:20980339

Abstract

OBJECTIVE

High viraemia of hepatitis B virus (HBV) influences all phases in the development of hepatocellular carcinoma (HCC). This study was designed to estimate the overall contribution of host genetics to HBV viraemia, and investigate the influence of common single-nucleotide polymorphisms (SNPs) in the interferon γ (IFNγ) signalling pathway, which is pivotal in the non-cytolytic clearance of HBV.

METHODS

We first determined familial correlations and heritability (ie, proportion of phenotypic variation that is attributable to additive genetic factors) for HBV viraemia using 280 HCC families, including 766 adult HBV carriers. Then family-based association analysis was conducted for viraemia with a panel of 40 SNPs across ten IFNγ-related genes. For replication, seven tagging SNPs in identified candidate regions were also tested in a further 1011 unrelated individuals with longitudinal data on HBV viraemia over 16 years.

RESULTS

After adjustment for HBV genotype and sex, significant correlations for viraemia were detected among both siblings and mother-child pairs. Heritability accounted for approximately 30% (p<0.0002) of the variance of viral load, whereas HBV genotype and sex together explained less than 3%. Heritability estimates increased up to 74.0% after further exclusion of subjects with episodes of liver biochemical abnormalities. Our initial family-based association analysis identified two SNPs (rs2284553 (intronic SNP) and rs9808753 (Q64R)) on the IFNγ receptor 2 (IFNGR2) gene that were robustly associated with viraemia after multitest correction (all p<0.02). The SNPs were also associated with the longitudinal levels of viraemia and the persistence of a high viraemia of ≥4.39 log copies/ml (all p<0.0001) in unrelated individuals.

CONCLUSIONS

HBV viraemia appears to have substantial heritability. Polymorphisms in the IFNGR2 gene appear to be associated with the variability of viraemia.

摘要

目的

乙型肝炎病毒（HBV）的高病毒血症影响肝癌（HCC）发展的所有阶段。本研究旨在评估宿主遗传学对 HBV 病毒血症的总体贡献，并研究干扰素 γ（IFNγ）信号通路中常见单核苷酸多态性（SNP）的影响，该通路在 HBV 的非细胞溶解清除中至关重要。

方法

我们首先使用包括 766 名成年 HBV 携带者在内的 280 个 HCC 家族，确定 HBV 病毒血症的家族相关性和遗传力（即表型变异归因于加性遗传因素的比例）。然后，对十个 IFNγ 相关基因的 40 个 SNP 进行基于家族的关联分析。为了验证，在具有 16 年 HBV 病毒血症纵向数据的另外 1011 名无关个体中，还测试了确定的候选区域中的七个标记 SNP。

结果

在调整 HBV 基因型和性别后，在兄弟姐妹和母子对之间均检测到病毒血症的显著相关性。遗传力占病毒载量变异的约 30%（p<0.0002），而 HBV 基因型和性别共同解释的不到 3%。在进一步排除有肝脏生化异常发作的受试者后，遗传力估计值增加到 74.0%。我们的初步基于家族的关联分析确定了 IFNγ 受体 2（IFNGR2）基因上的两个 SNP（rs2284553（内含子 SNP）和 rs9808753（Q64R）），在多测试校正后与病毒血症具有稳健相关性（均 p<0.02）。这些 SNP 还与病毒血症的纵向水平以及≥4.39 log 拷贝/ml 的高病毒血症持续存在相关（均 p<0.0001）。