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

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