Genetic variations underlying Gilbert syndrome and HBV infection outcomes: a cross-sectional study.
Genetic variations underlying Gilbert syndrome and HBV infection outcomes: a cross-sectional study.
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DOI：
10.3389/fgene.2023.1265268
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发表时间：
2023
影响因子：
3.7
通讯作者：
Han, Yue
中科院分区：
文献类型：
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作者：
Yao, Bilian;Xu, Qi;Zhang, Xinxin;Han, Yue
关键词：
背景：持续的细胞损伤导致乙型肝炎病毒（HBV）感染的预后不良。越来越多的证据表明胆红素具有细胞保护特性。在这里，我们研究了 UDP 葡萄糖醛酸基转移酶家族 1 成员 A1 (UGT1A1)（吉尔伯特综合征 (GS) 的遗传原因，吉尔伯特综合征 (GS) 是轻度非结合胆红素血症的常见病症）与 HBV 感染结果之间的关系。 方法：对2015年1月至2023年5月瑞金医院收治的非结合高胆红素血症患者2792例进行HBV感染及宿主UGT1A1变异筛查，并纳入确诊的HBV暴露患者。对 UGT1A1 的启动子/外显子/相邻内含子区域进行测序。比较了野生型和变异型 UGT1A1 宿主之间的 HBV 感染结果。使用三种分类方法评估 UGT1A1 变异的影响程度。 结果：总共招募了 175 名确诊 HBV 暴露的患者进行最终分析。 UGT1A1野生型和致病变异组之间的年龄、性别、HBV血清学标志物水平和抗病毒治疗具有可比性。检测到五种已知的致病突变（UGT1A1*28、UGT1A1*6、UGT1A1*27、UGT1A1*63 和 UGT1A1*7）。 UGT1A1 变异宿主中肝硬化或肝细胞癌 (LC/HCC) 的发生率显着低于 UGT1A1 野生型宿主（13.14% vs. 78.95%，p < 0.0001）。患者的 UGT1A1 变异越罕见，诊断 LC/HCC 的年龄就越高（R = 0.34，p < 0.05）。相比之下，只有 UGT1A1 变异组中才发现未出现 HBsAg 清除的无肝硬化患者（12.32% vs. 0%）。 结论：这项研究的结果提供了对先前存在的遗传性轻度胆红素升高与病毒感染结果之间的关联的见解。我们发现 UGT1A1 变异的积累或变异的稀有性与更好的预后相关，并且影响程度与 UGT1A1 缺乏相关。这项研究证明了 GS 基础上的宿主 UGT1A1 变异对 HBV 感染结果的治疗潜力。
Background: Constant cellular damage causes a poor prognosis of hepatitis B virus (HBV) infection. Accumulating evidence indicates the cytoprotective properties of bilirubin. Here, we investigated the association of UDP glucuronosyltransferase family 1 member A1 (UGT1A1), the genetic cause of Gilbert syndrome (GS), a common condition of mild unconjugated bilirubinemia, with HBV infection outcomes. Methods: Patients (n = 2,792) with unconjugated hyperbilirubinemia were screened for HBV infection and host UGT1A1 variations in Ruijin Hospital from January 2015 to May 2023, and those with confirmed HBV exposure were included. The promoter/exons/adjacent intronic regions of UGT1A1 were sequenced. HBV infection outcomes were compared between hosts with wild-type and variant-type UGT1A1. The effect magnitudes of UGT1A1 variations were evaluated using three classification approaches. Results: In total, 175 patients with confirmed HBV exposure were recruited for final analysis. Age, gender, level of HBV serological markers, and antiviral treatment were comparable between UGT1A1 wild-type and disease-causing variation groups. Five known disease-causing mutations (UGT1A1*28, UGT1A1*6, UGT1A1*27, UGT1A1*63, and UGT1A1*7) were detected. The incidence of cirrhosis or hepatocellular carcinoma (LC/HCC) was significantly lower in UGT1A1 variant hosts than in UGT1A1 wild-type hosts (13.14% vs. 78.95%, p < 0.0001). The rarer the UGT1A1 variation a patient possessed, the higher the age at which LC/HCC was diagnosed (R = 0.34, p < 0.05). In contrast, patients without cirrhosis achieving HBsAg clearance were identified only in the UGT1A1 variant group (12.32% vs. 0%). Conclusion: The findings of this study provide insights into the association between preexisting genetically mild bilirubin elevation and viral infection outcome. We showed that the accumulation of UGT1A1 variants or the rarity of the variation is associated with a better prognosis, and the effect magnitude correlates with UGT1A1 deficiency. This study demonstrates the therapeutic potential of host UGT1A1 variations underlying GS against HBV infection outcomes.
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