AUTHOR=Yao Bilian , Xu Qi , Zhang Xinxin , Han Yue 

TITLE=Genetic variations underlying Gilbert syndrome and HBV infection outcomes: a cross-sectional study

JOURNAL=Frontiers in Genetics

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1265268

DOI=10.3389/fgene.2023.1265268

ISSN=1664-8021

ABSTRACT=<p><bold>Background:</bold> 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 <italic>UDP glucuronosyltransferase family 1 member A1</italic> (<italic>UGT1A1</italic>), the genetic cause of Gilbert syndrome (GS), a common condition of mild unconjugated bilirubinemia, with HBV infection outcomes.</p><p><bold>Methods:</bold> Patients (n = 2,792) with unconjugated hyperbilirubinemia were screened for HBV infection and host <italic>UGT1A1</italic> 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 <italic>UGT1A1</italic> were sequenced. HBV infection outcomes were compared between hosts with wild-type and variant-type <italic>UGT1A1</italic>. The effect magnitudes of <italic>UGT1A1</italic> variations were evaluated using three classification approaches.</p><p><bold>Results:</bold> 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 <italic>UGT1A1</italic> wild-type and disease-causing variation groups. Five known disease-causing mutations (<italic>UGT1A1*28</italic>, <italic>UGT1A1*6</italic>, <italic>UGT1A1*27</italic>, <italic>UGT1A1*63</italic>, and <italic>UGT1A1*7</italic>) were detected. The incidence of cirrhosis or hepatocellular carcinoma (LC/HCC) was significantly lower in <italic>UGT1A1</italic> variant hosts than in <italic>UGT1A1</italic> wild-type hosts (13.14% vs<italic>.</italic> 78.95%, <italic>p &lt; 0.0001</italic>). The rarer the <italic>UGT1A1</italic> variation a patient possessed, the higher the age at which LC/HCC was diagnosed (R = 0.34, <italic>p</italic> &lt; 0.05). In contrast, patients without cirrhosis achieving HBsAg clearance were identified only in the <italic>UGT1A1</italic> variant group (12.32% vs. 0%).</p><p><bold>Conclusion:</bold> 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 <italic>UGT1A1</italic> variants or the rarity of the variation is associated with a better prognosis, and the effect magnitude correlates with <italic>UGT1A1</italic> deficiency. This study demonstrates the therapeutic potential of host <italic>UGT1A1</italic> variations underlying GS against HBV infection outcomes.</p>