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四重突变 GCAC1809-1812TTCT 可作为健康欧洲 HBV 携带者的生物标志物。

Quadruple mutation GCAC1809-1812TTCT acts as a biomarker in healthy European HBV carriers.

机构信息

Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany.

Paul Ehrlich Institute, Division of Virology, Langen, Germany.

出版信息

JCI Insight. 2020 Nov 19;5(22):135833. doi: 10.1172/jci.insight.135833.

DOI:10.1172/jci.insight.135833
PMID:33055418
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7710305/
Abstract

Many mutation analyses of the HBV genome have been performed in the search for new prognostic markers. However, the Kozak sequence preceding precore was covered only infrequently in these analyses. In this study, the HBV core promoter/precore region was sequenced in serum samples from European inactive HBV carriers. Quadruple mutation GCAC1809-1812TTCT was found with a high prevalence of 42% in the Kozak sequence preceding precore among all HBV genotypes. GCAC1809-1812TTCT was strongly associated with coexistence of basal core promoter (BCP) double mutation A1762T/G1764A and lower HBV DNA levels. In vitro GCAC1809-1812TTCT lead to drastically diminished synthesis of pregenomic RNA (pgRNA), precore mRNA, core, HBsAg, and HBeAg. Calculation of the pgRNA secondary structure suggests a destabilization of the pgRNA structure by A1762T/G1764A that was compensated by GCAC1809-1812TTCT. In 125 patients with HBV-related cirrhosis, GCAC1809-1812TTCT was not detected. While a strong association of GCAC1809-1812TTCT with inactive carrier status was observed, BCP double mutation was strongly correlated with cirrhosis, but this was only observed in absence of GCAC1809-1812TTCT. In conclusion, our data reveal that GCAC1809-1812TTCT is highly prevalent in inactive carriers and acts as a compensatory mutation for BCP double mutation. GCAC1809-1812TTCT seems to be a biomarker of good prognosis in HBV infection.

摘要

许多针对 HBV 基因组的突变分析都在寻找新的预后标志物。然而，这些分析中很少涉及前核心区的 Kozak 序列。在这项研究中，对来自欧洲非活动性 HBV 携带者的血清样本进行了 HBV 核心启动子/前核心区测序。在所有 HBV 基因型中，前核心区 Kozak 序列中发现了高频的四重突变 GCAC1809-1812TTCT，其发生率为 42%。GCAC1809-1812TTCT 与基础核心启动子（BCP）双突变 A1762T/G1764A 的共存和 HBV DNA 水平较低密切相关。体外实验表明，GCAC1809-1812TTCT 导致前基因组 RNA（pgRNA）、前核心 mRNA、核心、HBsAg 和 HBeAg 的合成明显减少。对 pgRNA 二级结构的计算表明，A1762T/G1764A 导致 pgRNA 结构不稳定，而 GCAC1809-1812TTCT 则对此进行了补偿。在 125 例 HBV 相关肝硬化患者中，未检测到 GCAC1809-1812TTCT。虽然观察到 GCAC1809-1812TTCT 与非活动性携带者状态密切相关，但 BCP 双突变与肝硬化密切相关，但这种相关性仅在不存在 GCAC1809-1812TTCT 时观察到。总之，我们的数据表明，GCAC1809-1812TTCT 在非活动性携带者中高度流行，并且作为 BCP 双突变的补偿突变。GCAC1809-1812TTCT 似乎是 HBV 感染良好预后的生物标志物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eaf8/7710305/da2ca683238a/jciinsight-5-135833-g075.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eaf8/7710305/1d7e3bae1dc8/jciinsight-5-135833-g070.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eaf8/7710305/eae51e25502b/jciinsight-5-135833-g071.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eaf8/7710305/b0fe96961520/jciinsight-5-135833-g072.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eaf8/7710305/9d92262c060d/jciinsight-5-135833-g073.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eaf8/7710305/1483c997ea9b/jciinsight-5-135833-g074.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eaf8/7710305/da2ca683238a/jciinsight-5-135833-g075.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eaf8/7710305/1d7e3bae1dc8/jciinsight-5-135833-g070.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eaf8/7710305/eae51e25502b/jciinsight-5-135833-g071.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eaf8/7710305/b0fe96961520/jciinsight-5-135833-g072.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eaf8/7710305/9d92262c060d/jciinsight-5-135833-g073.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eaf8/7710305/1483c997ea9b/jciinsight-5-135833-g074.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eaf8/7710305/da2ca683238a/jciinsight-5-135833-g075.jpg

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