HLA-DPPolymorphisms Affect the Outcomes of Chronic Hepatitis B Virus Infections, Possibly through Interacting with Viral Mutations

Abstract

c Genetic polymorphisms of HLA-DP have been associated with hepatitis B virus (HBV) persistence. We aimed to determine the effect of HLA-DP polymorphisms on the generation of HBV mutations and their interactions on the outcomes of HBV infection. rs3077, rs3135021, rs9277535, and rs2281388 were genotyped in 1,342 healthy controls, 327 HBV clearance subjects, and 2,736 HBV-positive subjects, including 1,108 hepatocellular carcinoma (HCC) patients, using quantitative PCR. HBV mutations were determined by sequencing. Multiplicative interactions of HLA-DP polymorphisms and viral mutations were assessed by multivariate logistic regression. rs3077 (from subjects with genotype CT combined with those from subjects with genotype TT [CT؉TT] versus CC), rs3135021 (GA؉AA versus GG), rs9277535 (GA؉AA versus GG), and rs2281388 (CC versus CT؉TT) significantly decreased HBV persistence. This effect was found only in genotype B HBV-infected subjects compared to HBV clearance subjects. HLA-DP polymorphisms promoting HBV clearance were associated with a lower prevalence of mutations increasing HCC risk (C1653T, T1674C/G, A1846T, G1896A and pre-S2 mutations and pre-S deletion in genotype C) and a higher prevalence of mutations decreasing HCC risk (G1652A, T1673C, T1674C, G1719T, G1730C, and G1799C in genotype B and A1727T in genotype C). Significant effects of viral mutations on cirrhosis and HCC were selectively evident in those with HLA-DP polymorphisms promoting HBV persistence. The interactions of C1653T, T1674C/G, and G1896A mutations with HLA-DP polymorphisms promoting HBV clearance significantly decreased cirrhosis risk. The interaction of rs9277535 AA with the T1674C/G or G1719T mutation in genotype C significantly decreased HCC risk. In conclusion, HLA-DP polymorphisms affect genotype B HBV clearance, regulate immune selection of viral mutations, and influence cirrhosis and HCC risks contributed by HBV mutations. Chronic infection with hepatitis B virus (HBV) currently affects 350 million to 400 million people worldwide, and over 200,000 and 300,000 HBV-infected subjects die from decompensated hepatic cirrhosis (HC) and hepatocellular carcinoma (HCC), respectively, each year (1, 2). Chronic HBV infection results in approximately one-third of all HC cases and more than one-half of all HCC cases worldwide (3). The World Health Organization includes HBV in "group 1" human carcinogens (4). According to a sequence divergence of Ͼ8% in the entire genome, HBV has been classified into at least 8 genotypes so far. HBV genotypes have distinct geographic distributions and have been shown to differ with regard to clinical liver diseases, outcomes, and responses to interferon treatment (5). In East Asia, where HBV genotypes B and C are endemic, viral factors of HBV, including genotype C infection, hepatitis B virus e antigen (HBeAg) expression, high viral load (Ͼ10 4 copies/ml), and mutations in the enhancer II/basal core promoter/precore (EnhII/BCP/PC) and the pre-S regions, as well as active hepatic inflammation contribute greatly to ...

Virus evolution during chronic hepatitis B virus infection as revealed by ultradeep sequencing data

“…Virus mutations related to advanced liver disease seem to accumulate along the course of CHB Many of the virus mutations identified here affected genomic positions frequently associated with chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (Table 2) (Yin et al, 2011;Zhang et al, 2013). Remarkably, such mutations were present in both the inactive carrier patient and the immunotolerant ones, supporting the idea of a continuous diversification along the course of CHB, accompanied by the emergence of mutants associated with serious liver conditions.…”

“…Furthermore, all the study patients presented virus mutations, many of which have been shown recently to correlate with serious liver conditions (Table 2) (Yin et al, 2011;Zhang et al, 2013). The discovery of such mutations in immune-tolerant patients is novel and possibly has been hampered to date due to the limited sensitivity of traditional genotyping approaches (i.e.…”

Hepatitis B Virus Combo Mutations Improve the Prediction and Active Prophylaxis of Hepatocellular Carcinoma: A Clinic-Based Cohort Study

“…Of these mutations, A1762T/G1764A has been prospectively shown to be an independent risk factor of HCC (15,26). A1762T/ G1764A and A1762T/G1764A-based combo mutants are potentially selected by the immunocompromised microenvironment predisposed by genetic polymorphisms of key immune and proinflammatory molecules, and in turn promote an aggressive phenotype of HCC, as well as the recurrence of HCC after curative surgery (27)(28)(29)(30). The objective of this study was to clarify whether the baseline HBV mutations can predict the outcome of HBVinfected patients and whether HCC risk contributed by the HBV mutations can be selectively reduced by antiviral treatment.…”

Cancer Evo-Dev, a novel hypothesis derived from studies on hepatitis B virus-induced carcinogenesis

“…In our previous epidemiological studies, we found that the HLA-II genetic polymorphisms are statistically associated with the generation of the liver diseasesassociated HBV mutations. The HLA-DP polymorphisms rs3077 (CT + TT vs. CC), rs3135021 (GA + AA vs. GG), rs9277535 (GA + AA vs. GG), and rs2281388 (CC vs. CT + TT) significantly decrease HBV persistence in genotype B HBV-infected subjects; HLA-DP genotypes that promote HBV clearance are associated with a lower prevalence of HBV mutations increasing HCC risk (C1653T, T1674C/G, A1846T, G1896A, preS2 mutations, and preS deletion in genotype C) and a higher prevalence of HBV mutations decreasing HCC risk (G1652A, T1673C, T1674C, G1719T, G1730C, and G1799C in genotype B and A1727T in genotype C); furthermore, significant effects of HBV mutations on cirrhosis and HCC are selectively evident in those with the HLA-DP genotypes that promote HBV persistence [61] . Thus, the HLA-DP polymorphisms affect genotype B HBV clearance, regulate immune selection of viral mutations, and influence cirrhosis and HCC risks contributed by the HBV mutations.…”