Concurrence of novel mutations causing Gilbert's and Dubin-Johnson syndrome with poor clinical outcomes in a Han Chinese family.

Dual-hereditary jaundice (Dubin-Johnson syndrome (DJS) and Gilbert's syndrome (GS)) is a rare clinical entity resulting from defects of the ATP binding cassette subfamily C member 2 (ABCC2) and UDP glucuronosyltransferase family 1 member A1 (UGT1A1) genes with autosomal recessive inheritance. In this study, we aimed to investigate the mutation profiles and characterize the phenotypes in a Han Chinese family with DJS and GS. Genetic screening for variants in the ABCC2 and UGT1A1, immunohistochemistry for expression of ABCC2, and histopathological examination were carried out. The proband and his brother had unconjugated and conjugated hyperbilirubinemia after birth. The proband's sister had only conjugated hyperbilirubinemia after birth. The proband developed into pleural effusions and ascites, pericardial thickening, intrahepatic and extrahepatic biliary duct dilatation, and enlarged gallbladder at age 50. Hepatocellular carcinoma occurred in the proband's brother at age 46. Seven compound defects of the ABCC2 gene [c.2414delG, p.(Ile1489Gly), p.(Thr1490Pro), and p.(Ile1491Gln)] and the UGT1A1 gene (c.-3279T>G, p.(Gly71Arg), and p.(Pro451Leu)) were identified in family members. Accumulation of pigment in hepatocytes characteristic of that in DJS was present in the proband and his brother. Expression of ABCC2 protein was markedly diminished in the patient's liver. Our results show a different genetic profile of DJS and GS in a Han Chinese family, indicating a more complex pattern of dual-hereditary jaundice among different populations. The present study illuminates the underpinnings of DJS and GS and extends the mutation profiles and phenotypes of these two syndromes in dual-hereditary jaundice.

Mitochondrial DNA haplogroup F confers genetic susceptibility to chronic HBV infection for the Yi nationality in Lijiang, China.

Mitochondria are essential for hepatitis B virus (HBV) infection. Moreover, the findings of our previous study indicate that host mitochondrial genetic factors are associated with chronic hepatitis B (CHB) for the Han Chinese. However, in terms of genetic heterogeneity, the impact of mitochondria on host susceptibility to HBV infection in ethnic minorities in China remains unclear. Here, a total of 7070 subjects who had visited the hospital between June 1, 2019, and April 31, 2020, were enrolled for seroprevalence of HBV infection investigation. A total of 220 individuals with CHB (CHBs) and 223 individuals with a trace of HBV infection (spontaneously recovered subjects, SRs) were analyzed for mitochondrial DNA (mtDNA) sequence variations and classified into respective haplogroups. Haplogroup frequencies were compared between CHBs and SRs. Among eight nationalities, Yi nationality patients had the highest HBsAg prevalence rate (27.9% [95% CI: 25.3%-30.5%]) and the lowest vaccination rate (4.9% [95% CI: 3.7%-6.2%]). After adjustment for age and gender, haplogroup F was a risk factor for CHB infection (P = 0.049, OR = 2.079, 95% CI = 1.002-4.31), while D4 had a significant negative correlation with the HBeAg-positive rate (P = 0.024, OR = 0.215, 95% CI = 0.057-0.816). Together with our previous study, the findings indicate that different nationalities have different genetic susceptibility to HBV infection.

The association of the heterogeneity of HBV reverse transcriptase quasispecies with antiviral efficacy after treatment with nucleos(t)ide analogues for 10 years.

To assess the heterogeneity of HBV reverse transcriptase (RT) quasispecies during 10 years of antiviral therapy and their association with antiviral efficacy. Nineteen patients with chronic hepatitis B (CHB) infection receiving nucleos(t)ide analogues (NAs) were enrolled. Based on the antiviral efficacy after 1 year of treatment, 5 patients were grouped into an early virologic response (EVR) group, while 8 patients were grouped into a late virologic response (LVR) group. Furthermore, 6 CHB patients that had undergone antiviral treatment for 10 years were grouped into a virologic breakthrough (VBT) group. The HBV RT from each patient were amplified, cloned, and sequenced. The complexity of the RT gene in the EVR group was significantly higher than that in the LVR (P = 0.0393) and VBT groups (P = 0.0141). Phylogenetic tree analysis showed that the average branch length of the EVR and LVR groups were significantly greater than that of VBT group (P < 0.001). The complexity (at the nucleotide level) of the RT quasispecies was negatively correlated with the corresponding HBV DNA load (P = 0.0163) at one year post-antiviral treatment. Moreover, both the LVR and VBT groups accumulated more deleterious mutations than the EVR group. After 1 year of NAs treatment, the increased HBV quasispecies complexity and evolutionary topologies, coupled with less deleterious mutations, are likely associated with a favorable efficacy during long-term antiviral treatment.