Molecular Epidemiology of Hepatitis B Virus (HBV) Genotypes and Serotypes in Patients with Chronic HBV Infection in Korea

Kim²,

Kim

et al. 2013

J Clin Microbiol

Self Cite

bThe issue of hepatitis B virus (HBV) mutations possibly leading to a gender disparity in the progression of liver diseases has not been explored. We aimed to elucidate the relationships of the novel pre-S1 mutations, W4P/R, with the progression of liver diseases and male predominance in a South Korean chronic cohort by use of a molecular epidemiologic study. We developed a fluorescence resonance energy transfer (FRET)-based real-time PCR (RT-PCR) assay for the detection of the W4P/R mutations and applied it to 292 chronic HBV patients. The pre-S1 mutations from 247 (84.6%) of a total of 292 patients were detected by this assay. W4P/R mutants were found to be significantly related to severe liver diseases (hepatocellular carcinoma [HCC] and liver cirrhosis, 12.4% [19/153] of patients, versus chronic hepatitis and asymptomatic carriage, 1.1% [1/94] of patients) (P < 0.001). All of the W4P/R mutants were found in males only. The novel HBV pre-S1 mutations, W4P/R, may be associated with disease severity in male patients chronically infected with HBV genotype C. The W4P/R mutations may provide in part an explanation for the relatively high ratio of male to female incidence in HCC generation in South Korean chronic HBV patients. Hepatitis B virus (HBV) infection is a global health problem, and Ͼ350 million people are chronic carriers of the virus (1, 2). The infection is associated with a wide spectrum of clinical manifestations, ranging from acute or fulminant hepatitis to various forms of chronic infection, including asymptomatic carriage, chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) (3). South Korea is recognized as an area where HBV infection is endemic; based on the Korean National Health and Nutrition Survey of 2007, the prevalence of HBsAg was 4.2% in men and 3.1% in women at that time (4). Moreover, it was reported that the extraordinary prevalence in South Korea of HBV genotype C2, which is known to be more virulent than HBV genotype B (5), might contribute to the distribution of the characteristic HBV mutation patterns related to the progression of liver diseases (6-14).HBV produces three envelope proteins, all of which are encoded in the pre-S/S open reading frame. They have been suggested to play a role in virus assembly (15, 16) and attachment to hepatocytes (17). It has also been proposed that large surface proteins (LHBs) with mutations, particularly deletions, in the Pre-S region might contribute to hepatocarcinogenesis through the induction of an endoplasmic reticulum (ER) stress pathway or trans-activating capacity (18-20). HBV pre-S mutations prevail in countries where HBV infection is highly endemic. In general, the Pre-S2 region is known to be more prone to mutations than the Pre-S1 region. Therefore, so far, the mutation patterns related to the progression of liver disease have been described more frequently in the Pre-S2 than in the Pre-S1 region. Recently, we showed a novel pre-S1 deletion type leading to 11 amino acid deletions from the pre-S1 start codon that is related t...

Section: Figmentioning

confidence: 64%

mentioning

confidence: 99%

Male-Specific W4P/R Mutation in the Pre-S1 Region of Hepatitis B Virus, Increasing the Risk of Progression of Liver Diseases in Chronic Patients

Kim²,

Kim

et al. 2013

J Clin Microbiol

Self Cite

“…Almost all Korean HBV genotypes are known to be HBV C2 (16) and, unfortunately, patients with HBV C2 genotype tend to rapidly progress to cirrhosis or HCC, and it can commonly cause complications in younger patients (12).…”

Section: Discussionmentioning

confidence: 99%

Impact of Hepatitis B Virus (HBV) X Gene Mutations on Hepatocellular Carcinoma Development in Chronic HBV Infection

Han

et al. 2011

Clin. Vaccine Immunol.

The hepatitis B virus (HBV) PreS mutations C1653T, T1753V, and A1762T/G1764A were reported as a strong risk factor of hepatocellular carcinoma (HCC) in a meta-analysis. HBV core promoter overlaps partially with HBx coding sequence, so the nucleotide 1762 and 1764 mutations induce HBV X protein (HBx) 130 and 131 substitutions. We sought to elucidate the impact of HBx mutations on HCC development. Chronically HBV-infected patients were enrolled in this study: 42 chronic hepatitis B (CHB) patients, 23 liver cirrhosis (LC) patients, and 31 HCC patients. Direct sequencing showed HBx131, HBx130, HBx5, HBx94, and HBx38 amino acid mutations were common in HCC patients. Of various mutations, HBx130؉HBx131 (double) mutations and HBx5؉HBx130؉HBx131 (triple) mutations were significantly high in HCC patients. Double and triple mutations increased the risk for HCC by 3.75-fold (95% confidence interval [CI] ‫؍‬ 1.101 to 12.768, P ‫؍‬ 0.033) and 5.34-fold (95% CI ‫؍‬ 1.65 to 17.309, P ‫؍‬ 0.005), respectively, when HCC patients were compared to CHB patients. Functionally, there were significantly higher levels of NF-B activity in cells with the HBx5 mutant and with the double mutants than that of wild-type cells and the triple-mutant cells. The triple mutation did not increase NF-B activity. Other regulatory pathways seem to exist for NF-B activation. In conclusion, a specific HBx mutation may contribute to HCC development by activating NF-B activity. The HBx5 mutation in genotype C2 HBV appears to be a risk factor for the development of HCC and may be used to predict the clinical outcomes of patients with chronic HBV infection.Hepatitis B virus (HBV) infection is a global health issue, with two billion people infected worldwide and 350 million suffering from chronic HBV infection (18). Chronic HBV infection is known as the most common underlying etiology of hepatocellular carcinoma (HCC) (2) and can further progress to liver cirrhosis (LC) and HCC. However, the pathogenesis of these HBV-related diseases has not been fully clarified. The disease progression may depend on complex and multistep mechanisms.In an HBV management consensus report, the National Institutes of Health (NIH) suggested risk factors associated with the increased risk of HCC and cirrhosis in chronic HBVinfected patients (20). That report described the HCC risk based on demographic factors, environmental factors, and viral factors and classified them using the scoring system of evidence-based studies. The association between HBV mutations and HCC has not been fully investigated. Recently, the HBV PreS mutations C1653T, T1753V, and A1762T/G1764A were reported as strong risk factors for HCC in a meta-analysis (19). Mutations of HBV have been considered as an escape mechanism from the host immune system and may affect the oncogenic potential of chronic HBV diseases.HBV X is the smallest of four kinds of HBV functional genes, but it expresses a 154-amino-acid multifunctional protein (HBx), with an N-terminal negative regulatory/antiapoptotic domain and a C-termin...

“…For example, genotype C strains have a higher capacity to induce more progressive forms of liver disease and are more prone to the development of mutations than genotype B strains (20). Thus, the extraordinary prevalence of the genotype C characteristic of Korean patients with chronic liver disease could affect mutation patterns or frequencies of Korean HBV strains (13). Actually, relatively higher mutation frequencies in basal core promoter (BCP) (23,27) and in the major hydrophilic region (MHR) have been reported in Korean patients.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, it was reported that the extraordinary prevalence of genotype C2 in this area, which is known to be more virulent than genotype B (5), might contribute to distribution of the characteristic HBV mutation patterns related to progression of liver diseases (13,14,19,24).…”

mentioning

confidence: 99%

Novel F141L Pre-S2 Mutation in Hepatitis B Virus Increases the Risk of Hepatocellular Carcinoma in Patients with Chronic Genotype C Infections

Mun

Kim

et al. 2011

J Virol

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Several lines of evidence have suggested that some naturally occurring mutations of hepatitis B virus (HBV) play a critical role in hepatocellular carcinoma (HCC). Here, we describe a novel HCC-related pre-S2 mutation, F141L. To prove the relationship between the F141L mutation and HCC, molecular epidemiology studies using MboII PCR restriction analysis (PRA) were performed, and the molecular mechanism was investigated through construction of a stable hepatocyte cell line expressing the large surface HB protein (LHB) with the F141L mutation (F141L-LHB). Application of MboII PRA to samples from 241 Korean patients with chronic liver diseases of different clinical stages confirmed that F141L mutants were significantly related to HCC, even in comparison to liver cirrhosis (HCC, 26.3% of patients, or 26/99; liver cirrhosis, 3.8% of patients, or 2/52; P ‫؍‬ 0.001). By studying stable cell lines, we found that F141L-LHBs could induce cell cycle progression by downregulating the p53 and p21 pathways and upregulating CDK4 and cyclin A. Furthermore, we found that in a colony-forming assay, the colony-forming rates in cell lines expressing F141L-LHBs were about twice as high as those of the wild type. In conclusion, our results suggest that F141L-LHBs may contribute importantly to the pathogenesis of HCC by inducing cell proliferation and transformation. So, the F141L mutation examined in this study could serve as a diagnostic marker for the prognosis of HCC.Hepatitis B virus (HBV) infection is a global health problem. Roughly 2 billion people, one-third of the world's population, have serological evidence of infection. Worldwide, the 350 million people with chronic HBV infection have a 15% to 25% risk of dying from HBV-related liver disease, including end-stage cirrhosis and hepatocellular carcinoma (HCC). Each year, acute and chronic HBV infections cause roughly 1 million deaths (12). Although most carriers will not develop hepatic complications from chronic hepatitis B, 15% to 40% will develop serious sequelae during their lifetimes (17).The clinical expression of hepatitis B in different parts of the world depends not only on the prevalent genotypes but also on the prevalent modes of transmission. In Western countries, HBV infection is relatively rare and is acquired primarily in adulthood, with a low rate of progression to chronicity, rarely, if ever, leading to HCC, whereas in Asia and most of Africa, chronic HBV infection is common and usually acquired perinatally or in childhood and is associated with a high rate of progression to cirrhosis and cancer. The difference in the natural course of infection is mediated by the interaction between virus and host, which is largely determined by the age at which the infection is acquired (18).South Korea is recognized and an area of endemicity for of HBV infection, and based on the Korean National Health and Nutrition Survey of 1998, the prevalence of hepatitis B surface antigen (HBsAg) was 5.1% in men and 4.1% in women (4). Moreover, it was reported that the extraordinary ...