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1.
Mikrobiyol Bul ; 54(1): 66-78, 2020 Jan.
Artigo em Turco | MEDLINE | ID: mdl-32050879

RESUMO

It has been estimated that currently 350-400 million people have been chronically infected with the hepatitis B virus (HBV) worldwide and approximately one million people die each year due to HBV related diseases. It has been suggested that the viral and host factors, especially the host immune system, may play a role in the chronicity of the HBV infection. Stimulator of interferon genes (STING) is one of the members of the pattern recognition receptor (PRR) that detects the presence of DNA in a human cell, activate synthesis of various cytokines and this protein is thought to be an important member of the immune system against HBV infection. Based on the assumption that there may be a relationship between the differences of STING expression in individuals and HBV chronicity, the aim of this study was to investigate STING gene expression levels in individuals naturally immunized against HBV, in chronic hepatitis B infected patients and in normal individuals who have not been exposed to HBV. A total of 90 volunteers have been included in the study from the age range of 18 to 65, in which the first group consists of 30 individuals naturally immunized against HBV, the second group consists of 30 chronically hepatitis B infected patients while the third group consists of 30 healthy population members who have not been exposed to HBV. Whole blood samples were taken from each participant and peripheral blood mononuclear cells (PBMC) were isolated afterwards. Total RNA was isolated from PBMC. After the synthesis of cDNA from the total RNA, STING gene expression levels were determined by real time polymerase chain reaction (Rt-PCR) method. Normalization was performed by applying the 2-ΔΔCT formula after Rt-PCR procedure. STING expression level of the naturally immunized group was calculated as 0.084 ± 0.026 on average, average STING expression level of healthy population group was 0.082 ± 0.032 and STING expression level of chronically infected patients group was 0.075 ± 0.022 on average. There was no statistically significant difference between the groups (p> 0.05). To our knowledge, this is the first study investigating the role of STING expression in the chronicity of HBV. Although there was no statistically significant difference between the groups, the data that showed STING expression levels in naturally immunized individuals were approximately 10% higher than those in chronic hepatitis B patients and was considered as an important finding.


Assuntos
Hepatite B Crônica , Hepatite B , Imunidade Inata , Proteínas de Membrana , DNA Viral , Hepatite B/genética , Vírus da Hepatite B , Hepatite B Crônica/genética , Humanos , Imunidade Inata/genética , Interferons , Leucócitos Mononucleares , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , RNA Mensageiro/genética
2.
Anticancer Res ; 40(1): 245-252, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892573

RESUMO

AIM: It has been shown that the integration of hepatitis B virus (HBV) gene into the host genome is a high-risk factor for development of hepatocellular carcinoma (HCC). However, the relationship between HBV S-integrated human extra spindle pole bodies-like 1 (ESPL1) gene and HCC is unknown. This study was designed to detect HBV S-integrated human ESPL1 fusion gene in patients with HCC for potentially using this fusion gene as a biomarker for HCC diagnosis. PATIENTS AND METHODS: Nineteen and 70 patients with chronic hepatitis B (CHB) were recruited to the experimental and control groups, respectively, and both groups underwent an effective nucleoside/nucleotide analog therapy and follow-up for HCC occurrence for up to 11 years. HCC tissues were obtained by surgical resection from the experimental group, while liver tissues were collected by liver biopsy in the control group prior to treatment with nucleoside/nucleotide analogs. Alu polymerase chain reaction was used to assess HBV S gene integration in the liver tissues from both groups. HBV S-integrated human ESPL1 fusion gene was then detected in patients with HBV S gene integration using a gene database. RESULTS: All patients in the experimental group developed HCC, whereas no HCC was diagnosed in the control group. HBV S gene integration was identified in 12 out of 19 HCC tissues in the experimental group, giving a detection rate of 63.2%, which was significantly greater than that of 15.7% (11/70) in the control group (p<0.001). We further showed that HBV S-integrated human ESPL1 fusion gene was detected in eight patients (rate of 66.7%) among the 12 patients with HCC with HBV S gene integration in the experimental group, whereas the fusion gene was not detectable in any of the patients in the control group (p=0.001). CONCLUSION: This research demonstrates a high detection rate of HBV S-integrated human ESPL1 fusion gene in patients with HBV-related HCC and shows that this fusion gene appears to be associated with HCC development in patients with CHB. These findings suggest that HBV S-integrated human ESPL1 fusion gene may potentially serve as a biomarker for early detection of HCC in HBV-infected populations.


Assuntos
Grupo com Ancestrais do Continente Asiático , Vírus da Hepatite B/genética , Neoplasias Hepáticas/genética , Proteínas de Fusão Oncogênica/genética , Separase/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Feminino , Regulação Neoplásica da Expressão Gênica , Hepatite B Crônica/genética , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/metabolismo , Separase/metabolismo , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo
3.
Immunology ; 159(2): 178-182, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31613998

RESUMO

Hepatitis B virus (HBV) infection causes a self-limiting disease in most individuals. However, < 10% of infected subjects develop a chronic disease. Genetic host variability of polymorphic genes at the interface of innate and acquired immunity, such as killer immunoglobulin-like receptors (KIR), their human leucocyte antigen (HLA) and IgG allotypes (GM), could explain this different clinical picture. We previously showed a protective role of the KIR2DL3 gene for the development of chronic hepatitis B (CHB), and a detrimental role of the KIR ligand groups, HLA-A-Bw4 and HLA-C2. We have expanded the previous analysis genotyping patients for GM23 and GM3/17 allotypes. The comparison of the patients with CHB with those who resolved HBV infection showed that the presence of GM17 allele virtually eliminated the risk of developing CHB (OR, 0·03; 95% CI, 0·004-0·16; P < 0·0001). In addition, the combination of GM17, KIR2DL3, HLA-A-Bw4 and HLA-C2 was highly sensitive to predict the outcome of HBV infection.


Assuntos
Antígenos HLA-B/genética , Antígenos HLA-C/genética , Hepatite B Crônica/prevenção & controle , Alótipos da Imunoglobulina Gm/genética , Receptores KIR2DL3/genética , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Antígenos HLA-B/imunologia , Antígenos HLA-C/imunologia , Vírus da Hepatite B/imunologia , Hepatite B Crônica/genética , Hepatite B Crônica/imunologia , Interações Hospedeiro-Patógeno , Humanos , Alótipos da Imunoglobulina Gm/imunologia , Fenótipo , Fatores de Proteção , Receptores KIR2DL3/imunologia , Medição de Risco , Fatores de Risco
4.
Medicine (Baltimore) ; 98(51): e17936, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31860948

RESUMO

Clearance of the hepatitis B surface antigen (HBsAg) is the ultimate aim of treatment for patients with chronic hepatitis B (CHB) infection. Genetic, factor age, and gender were reported to be involved in the clearance of HBsAg. However, the rate of HBsAg seroclearance in CHB patients is still low globally and few of the single-nucleotide polymorphism (SNP) had been identified to associated with HBsAg seroclearance in CHB patients.Recently, 3 associated SNPs (rs7944135, rs171941, and rs6462008) were reported in the clearance of HBsAg in the Korean population. However, these SNPs have not been investigated in the CHB Taiwanese population. In present study, these 3 SNPs were genotyped in 2565 Taiwanese CHB patients including 493 CHB patients with HBsAg seroclearance and 2072 without HBsAg seroclearance.We observed that SNP rs7944135 was solely associated with HBsAg seroclearance. Subjects with the AA genotype at rs7944135 of macrophage-expressed gene 1 had a higher susceptibility to HBsAg clearance, compared to those with the AG or GG genotype under the genotypic model (odds ratio [OR] = 1.76. 95% confidence interval [CI] = 1.14-2.72, P = .045). Furthermore, we found a 1.74-fold increased risk of acquiring HBsAg seroclearance associated with the AA genotype compared to AG + GG of rs7944135 under the recessive model (OR = 1.74. 95% CI = 1.13-2.66, P = .014). According to the cumulative fraction curve with the log-rank test revealed that patients with the AA genotype of rs7944135 showed higher susceptibility to occur HBsAg seroclearance (P = .039) and HBV DNA undetectable (P = .0074) compared to those with the AG or GG genotype.This study examined the associations of 3 SNPs (rs7944135, rs171941, and rs6462008) with HBsAg seroclearance, and we identified that rs7944135 is solely associated with HBsAg seroclearance in Taiwanese CHB patients.


Assuntos
Regulação da Expressão Gênica , Antígenos de Superfície da Hepatite B/genética , Vírus da Hepatite B/genética , Hepatite B Crônica/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Estudos de Coortes , Intervalos de Confiança , DNA Viral/análise , DNA Viral/genética , Feminino , Genótipo , Antígenos de Superfície da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Hepatite B Crônica/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único/imunologia , Estudos Retrospectivos , Testes Sorológicos/métodos , Taiwan
5.
Medicine (Baltimore) ; 98(44): e17867, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31689880

RESUMO

AIMS: Interleukin(IL)-22 plays an important role in promoting liver regeneration and repair, but its role in chronic HBV-related liver diseasesis not clear. The goal of this study was to evaluate associations between eight IL22 single nucleotide polymorphisms (SNPs) and the development of chronic HBV cirrhosis and HBV-related HCC within a Chinese Han population. METHODS: We investigated associations between single nucleotide polymorphisms (SNPs) in the IL22 gene (rs1026788, rs2227472, rs2227491, rs2227485, rs1179249, rs2046068,rs2227473, and rs7314777) and the risk of HBV-related chronic liver diseases within a Han population in Northeast China. A total of 649 participants were included in the study, including 103 patients with CHB, 264 patients with LC, and 282 patients with HCC. The odds ratios (OR) and corresponding 95% confidence intervals (CI) were calculated using chi-square test. Haplotype analysis was conducted by haploview software. RESULTS: Genotype and allele distributions of SNPs rs1179249 and rs2227472 differed between LC and CHB groups (both P < 0.05).The G alleles of SNP rs2227491 and rs1026788 were more frequent in the LC group than in the CHB group (P = 0.046, P = 0.041 respectively). A IL22 haplotype consisting of the minor alleles of SNP rs1179249 and the major alleles of seven other SNPs occurred less frequently in the LC and HCC groups than in the CHB group (28.2%, 33.94%, and 37.86%, respectively, P < 0.05). Moreover, there were no significant associations between smoking or drinking and IL22 SNPs on the risk of HCC (P > 0.05). CONCLUSION: IL22 genetic variations were associated with chronic HBV infection progression, especially in the HBV-LC group. The IL22 genetic variations may help clinicians initiate the correct treatment strategy at the CHB stage.


Assuntos
Carcinoma Hepatocelular/virologia , Hepatite B Crônica/genética , Interleucinas/genética , Cirrose Hepática/virologia , Neoplasias Hepáticas/virologia , Polimorfismo de Nucleotídeo Único , Adulto , Consumo de Bebidas Alcoólicas/efeitos adversos , Grupo com Ancestrais do Continente Asiático/genética , Carcinoma Hepatocelular/genética , Estudos de Casos e Controles , Progressão da Doença , Feminino , Hepatite B Crônica/complicações , Humanos , Cirrose Hepática/genética , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , Mutação Puntual , Estudos Retrospectivos , Fumar/efeitos adversos
7.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 44(8): 845-849, 2019 Aug 28.
Artigo em Chinês | MEDLINE | ID: mdl-31570669

RESUMO

OBJECTIVE: To detect the levels of miR-146a and miR-155 in different samples from chronic hepatitis B (CHB), reveal whether there is a correlation between the 2 miRNAs in different samples, and to provide a theoretical basis for sample choice of miRNA research in liver.
 Methods: Real-time PCR was conducted to examine the expression of miR-146a and miR-155 in the plasma, peripheral blood mononuclear cell (PBMC), and liver tissues from 41 CHB patients who underwent nucleoside analogues antiviral therapy for 104 weeks. Correlations between the levels of miR-146a and miR-155 among the 3 samples were analyzed.
 Results: The expressions of miR-146a and miR-155 in the plasma, PBMC and liver tissues were significantly down-regulated at the 104th week than those at the baseline (all P<0.05). There was a correlation in the expression of miR-146a between plasma and liver tissues (r=0.560, P=0.007), PBMC and liver tissues (r=0.428, P=0.047) at baseline. There was a correlation in the expression of miR-155 between plasma and liver tissue (r=0.587, P=0.004), PBMC and liver tissue (r=0.483, P=0.023) at baseline. The expressions of miR-146a and miR-155 between the plasma and PBMC were not correlated (P>0.05).
 Conclusion: Compared with PBMC, miR-146a and miR-155 from plasma can better reflect the expression in the liver tissues, suggesting that plasma can be applied in the mechanism research on miR-146a and miR-155 in the liver diseases instead of liver tissues.


Assuntos
Hepatite B Crônica , MicroRNAs/genética , Hepatite B Crônica/genética , Humanos , Leucócitos Mononucleares , Reação em Cadeia da Polimerase em Tempo Real
8.
BMC Immunol ; 20(1): 27, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31390978

RESUMO

BACKGROUND: Immune inhibitory receptors play an important role in chronic infections. However, little is known about their role in hepatitis B virus (HBV) infection. Here, we analyzed the relationship between programmed death-1 (PD-1) and lymphocyte activation gene-3 (LAG-3) expression on CD4+ T cells and HBV disease progression. RESULTS: PD-1 and LAG-3 expression was significantly higher on CD4+ T cells from HBV patients than on those from the HCs. In addition, a significant positive correlation was found between the PD-1 and LAG-3 expression levels and the ALT(alanine aminotransferase) level. CD4+ T cell function was inhibited by high PD-1 and LAG-3 levels, and CD4+ T cells with high PD-1 and LAG-3 expression lost the ability to secrete IFN-γ, IL-2 and TNF-α. Furthermore, blockade of the PD-1 and LAG-3 pathways reversed the damage to CD4+ T cell proliferation and cytokine secretion. CONCLUSIONS: CD4+ T cell exhaustion during chronic HBV had high PD-1 and LAG-3 expression and the absence of helper T cell cytokines, including IFN-γ, IL-2 and TNF-α. After blocking PD-L1 and LAG-3, CD4+ T cell function in chronic hepatitis B patients was partially restored.


Assuntos
Antígenos CD/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Vírus da Hepatite B/imunologia , Hepatite B Crônica/genética , Hepatite B Crônica/imunologia , Receptor de Morte Celular Programada 1/genética , Adulto , Antígenos CD/metabolismo , Antineoplásicos Imunológicos/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica , Vírus da Hepatite B/genética , Hepatite B Crônica/virologia , Humanos , Testes de Função Hepática , Ativação Linfocitária , Masculino , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Carga Viral
9.
Turk J Gastroenterol ; 30(7): 616-623, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31290749

RESUMO

BACKGROUND/AIMS: About 400 million people worldwide have been exposed to Hepatitis B (HBV) infection. A range of 10%-15% of chronic HBV carriers may present with various liver diseases including cirrhosis and hepatic cancer. The chronicity or clearance of HBV infection is dependent on viral and genetic variables. Genome-wide association studies (GWAS) have reported that the variants of human leukocyte antigen (HLA), rs3128917 and rs9380343, are significantly related to persistent HBV infection. HLA molecules are responsible for introducing various antigens into the immune system. These variants might affect antigen presentation by influencing HLA mRNA expression, therefore, antigen presentation may not be performed properly. This study aims to assess the relationship of HLA gene variants to chronic HBV infection. MATERIALS AND METHODS: HLA variants were explored in 238 chronic HBV patients and in 238 individuals with spontaneous clearance of HBV using PCR-RFLP assay. RESULTS: The allele and genotype of rs9380343 polymorphism were associated with persistent HBV infection risk (allele: p=0.038, genotype: p=0.029), but rs3128917 polymorphism was not significant. Additionally, rs9380343 polymorphism was also related to increased risk of HBV infection in males (p<0.05). CONCLUSION: The current study is the first report demonstrating the HLA rs9380343 polymorphism as a genetic risk factor for chronicity of HBV infection. Further independent studies are required to confirm the current findings using a larger sample size in different populations.


Assuntos
Antígenos HLA-DP/genética , Hepatite B Crônica/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Feminino , Genótipo , Antígenos HLA-DP/imunologia , Hepatite B Crônica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Turquia
10.
Mol Med Rep ; 20(3): 2177-2188, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31322199

RESUMO

The present study examined the relationships between the single nucleotide polymorphisms (SNPs) of three members of the apolipoprotein B mRNA­editing catalytic polypeptide­like 3 (A3) gene family, A3A, A3B and A3H, and hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC) in a Han Chinese population. A total of 654 patients were enrolled in the study between January 2012 and July 2016, including 104 patients with chronic HBV infection (CHB), 265 patients with HBV­related liver cirrhosis and 285 patients with HBV­related HCC. A total of two A3A SNPs (rs7286317 and rs7290153), three A3B SNPs (rs2267398, rs2267401 and rs2076109), and five A3H SNPs (rs56695217, rs139302, rs139297, rs139316 and rs139292) were genotyped using a MassArray system. Statistical analysis and haplotype estimation were conducted using Haploview and Unphased software. No significant associations were observed between the A3A, A3B and A3H SNPs and the development of CHB and HCC. Haplotype analysis revealed that the mutant haplotypes C­T­A, C­T­G, T­G­G and T­T­G from the A3B SNPs rs2267398­rs2267401­rs2076109 carried a lower risk of HCC than the reference haplotype. These findings suggested that there was no relationship between A3A, A3B and A3H SNPs and CHB progression or HCC development in the Han Chinese population.


Assuntos
Aminoidrolases/genética , Carcinoma Hepatocelular/genética , Citidina Desaminase/genética , Hepatite B Crônica/genética , Neoplasias Hepáticas/genética , Antígenos de Histocompatibilidade Menor/genética , Proteínas/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/virologia , China/epidemiologia , Feminino , Predisposição Genética para Doença , Hepatite B Crônica/complicações , Hepatite B Crônica/epidemiologia , Humanos , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
11.
Clin Lab ; 65(6)2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31232017

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the common lethal types of tumors all over the world. Overexpression of mircoRNA-224 (miR-224) has been reported to act as a potential biomarker for HCC patients. The goal of our study was to assess the prognostic impact of the expression and polymorphism of miR-224 in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients after liver resection. METHODS: A total of 62 cases of HBV-positive HCC patients, 17 HCC patients without HBV, and 13 healthy cases were enrolled in this study. Blood leukocyte miR-224 level were determined by qRT-PCR. Genotyping analysis of miR-224 rs188519172 was performed using an allele-specific PCR assay. All patients were undergoing partial liver resection and the prognostic values of miR-224 rs188519172 polymorphism for tumor development, survival rate, and liver injury after liver resection were examined. RESULTS: When we compared the blood leukocyte miR-224 level between HCC patients and healthy cases, we found that it was significantly increased in HCC patients. By subgroup analysis, it demonstrated that miR-224 expression was significantly increased in the HBV positive group compared with the HBV negative group. miR-224 rs188519172 AG + GG phenotype was significantly associated with severe liver injury after liver resection and patients carrying miR-224 rs188519172 AG + GG phenotype have a higher risk of cirrhosis and lower overall and disease-free survival rate. Meanwhile, the combination of miR-224 rs188519172 AG + GG phenotype and AFP value could improve the prognosis assessment of HBV related HCC. CONCLUSIONS: miR-224 rs188519172 polymorphism is an indicator of liver injury and a novel prognostic biomarker for tumor development and survival of HBV related HCC patients after liver resection.


Assuntos
Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Hepatite B Crônica/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/cirurgia , Feminino , Frequência do Gene , Genótipo , Hepatectomia , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/complicações , Hepatite B Crônica/virologia , Humanos , Estimativa de Kaplan-Meier , Cirrose Hepática/complicações , Cirrose Hepática/genética , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico
12.
PLoS One ; 14(6): e0218744, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31251754

RESUMO

The direct cytopathic effects of the hepatitis B virus (HBV) on subsequent liver damage are not fully understood in HBV-infected patients. However, associations between the prevalence of various HBV genotypes and the extent of liver damage have been reported from different parts of the world. The purpose of this study was to determine the distribution of HBV genotypes in patients with chronic HBV infection in Bangladesh, a country of 160 million people, of which approximately 3-6 million are chronically infected HBV patients. In addition, whole and partial genome sequencing of HBV was performed to evaluate the relationship between HBV mutations and genotypes. We found that 42% of the patients with low HBV DNA and normal levels of alanine aminotransferase (ALT) had HBV genotype D. In contrast, the HBV genotype C was dominant among patients with high HBV DNA levels (>2000 IU/ml) and elevated ALT and in patients with liver cirrhosis (LC) and hepatocellular carcinomas (HCC). Whole and partial genome sequences of HBV revealed that most patients with LC and HCC had HBV genotype C with mutations at the T1762/A1764 positions. It seems that Bangladesh represents a borderline country, situated within East Asia, which mainly consists of individuals with HBV genotypes B and C, whereas in the western parts of Asia, HBV genotypes A and D are prevalent. Bangladesh is, therefore, an excellent model for the comparison of the pathophysiology of three major HBV genotypes in a single population. The findings of this study suggest a possible association between HBV viral factors and the extent of liver damage in chronic HBV-infected patients.


Assuntos
Carcinoma Hepatocelular/virologia , Vírus da Hepatite B/genética , Hepatite B Crônica/virologia , Cirrose Hepática/virologia , Neoplasias Hepáticas/virologia , Mutação , Sequenciamento Completo do Genoma/métodos , Adolescente , Adulto , Alanina Transaminase/metabolismo , Bangladesh , Carcinoma Hepatocelular/metabolismo , DNA Viral/genética , Feminino , Estudos de Associação Genética , Genótipo , Vírus da Hepatite B/classificação , Hepatite B Crônica/genética , Hepatite B Crônica/metabolismo , Humanos , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Carga Viral , Adulto Jovem
13.
Virol Sin ; 34(5): 489-500, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31161555

RESUMO

The study was conducted to explore the mechanisms of sex differences in the response to chronic hepatitis B (CHB) in terms of DNA methylation, SNP genotype, and gene expression. Genomic DNA was isolated from peripheral blood mononuclear cells (PBMCs) of CHB patients and healthy controls and evaluated using the Human Methylation 450 K Assay. The DNA methylation level at hg37 chromosome (CHR) X: 7810800 was further validated using pyrosequencing. SNP genotypes, VCX mRNA expression of PBMCs, and plasma VCX protein concentration were further examined using SNaPshot, RT-qPCR, and Western blot, respectively. Results showed that a total of 5529 CpG loci were differentially methylated between male and female CHB patients. DNA methylation level and CC + CT frequency at CHR X: 7810800, VCX mRNA expression of PBMCs, and plasma VCX protein concentration were higher in female than in male CHB patients. The CHR X: 7810800 locus was hypermethylated in CHB patients with CC + CT genotypes in comparison with those with the TT genotype. In cases of CC + CT genotypes, VCX mRNA expression was negatively correlated with the DNA methylation level. CHB patients with higher levels of HBV DNA, AST, and GGT or higher GPRI scores exhibited lower VCX expression. In conclusion, SNPs and DNA methylation at the CHR X: 7810800 locus cooperatively regulate VCX expression in CHB. The upregulated VCX expression in female CHB patients might represent a mechanism of protection from more severe liver dysfunction and extensive fibrosis, as observed in male CHB patients.


Assuntos
Metilação de DNA , Hepatite B Crônica/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Fatores Sexuais , Adulto , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/sangue , Regiões Promotoras Genéticas , Regulação para Cima , Adulto Jovem
14.
Medicine (Baltimore) ; 98(23): e15924, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31169710

RESUMO

To explore interleukin-17 (IL-17) and its epigenetic regulation during the progression of chronic hepatitis B virus (HBV) infection.A total of 162 patients with chronic HBV infection, including 75 with chronic hepatitis B (CHB), 54 with hepatitis B-associated liver cirrhosis and 33 with hepatitis B-associated hepatocellular carcinoma (HBV-HCC), were enrolled in this study. Thirty healthy adults of the same ethnicity were enrolled in the control group. Whole venous blood was obtained from the patients and normal controls (n = 30). Clinical and laboratory parameters were assessed, and we performed enzyme-linked immunosorbent assay and quantitative real-time PCR to measure the serum levels and relative mRNA expression of IL-17, respectively. IL-17 promoter methylation in peripheral blood mononuclear cells was assessed by methylation-specific PCR. We analyzed the serum and mRNA levels of IL-17 and IL-17 promoter methylation in the 4 groups as well as the effect of methylation on serum IL-17 levels. Correlations between the IL-17 promoter methylation status and clinical parameters were analyzed by Spearman correlation analysis.Compared to the normal control group, the patient groups exhibited significantly higher serum and relative mRNA levels of IL-17. The methylation distribution among the patients was significantly lower than that among the normal controls (P < .05), with the HBV-HCC group showing the lowest IL-17 gene methylation frequency. The average IL-17 promoter CG methylation level was negatively correlated with IL-17 mRNA expression (r = -0.39, P = .03), and negative correlations between IL-17 promoter methylation and prothrombin time activity (r = -0.585, P = .035), alanine aminotransferase (r = -0.522, P < .01), aspartate aminotransferase (r = -0.315, P < .05), and the model for end-stage liver disease score (r = -0.461, P < .05) were observed. IL-17 serum levels in the methylated-promoter groups were significantly lower than those in the unmethylated-promoter groups.IL-17 expression and promoter methylation were associated with chronic HBV infection progression, especially in the HBV-HCC group. The IL-17 promoter status may help clinicians initiate the correct treatment strategy at the CHB stage.


Assuntos
Progressão da Doença , Vírus da Hepatite B , Hepatite B Crônica/genética , Interleucina-17/sangue , Regiões Promotoras Genéticas/genética , Adulto , Idoso , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Metilação de DNA , Epigênese Genética , Feminino , Hepatite B Crônica/sangue , Hepatite B Crônica/virologia , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/genética , Cirrose Hepática/virologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade
15.
Arch Virol ; 164(8): 2005-2013, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31102052

RESUMO

We previously found that genetic factors are associated with a familial predisposition for developing liver cirrhosis and hepatocellular carcinoma during chronic hepatitis B virus (HBV) infection. Autophagy has been shown to play a role in HBV replication and the course of disease. More than 190 host genes have been identified that modify the process of autophagy, but which of these genes are involved in chronicity of HBV infection and how this occurs remains unclear. Chronic hepatitis B (CHB) patients were recruited to investigate the expression of autophagy-modulating genes in peripheral blood mononuclear cells (PBMCs). mRNA prepared from PBMCs from members of two families with clustering HBV infection, including 11 CHB patients and nine healthy spouses, was hybridized to high-density oligonucleotide arrays. Immunoblot analysis was used to determine the level of autophagy. Of the 192 autophagy-modulating genes, 18 were found to be differently expressed. Of these, 11 displayed decreased expression in CHB patients, while seven displayed increased expression compared to those in healthy controls. Functional analysis showed that these genes are closely involved in initiation, nucleation, elongation of phagophores, formation of autophagosomes, transportation to lysosomes, and the process of degradation. Western blot analysis revealed inhibited autophagy in PBMCs based on decreased lipidation of LC3II. A differential expression profile of autophagy-modulating genes was observed, and decreased autophagy in PBMCs could be closely associated with chronicity of HBV infection, suggesting a novel strategy for the treatment of patients with chronic HBV infection.


Assuntos
Proteínas Relacionadas à Autofagia/genética , Autofagia/genética , Redes Reguladoras de Genes/genética , Hepatite B Crônica/genética , Leucócitos Mononucleares/fisiologia , Autofagossomos/fisiologia , Análise por Conglomerados , Feminino , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/virologia , Humanos , Lisossomos/fisiologia , Masculino , RNA Mensageiro/genética
16.
BMC Med Genet ; 20(1): 87, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31117968

RESUMO

BACKGROUND: Single nucleotide polymorphisms (SNPs) in the sodium taurocholate co-transporting polypeptide (NTCP) have been showed to be associated with natural history of hepatitis B virus (HBV) infection. However, it is unclear whether the SNPs are related to the clinical outcome of HBV infection in Thai individuals. METHODS: The rs2296651 and rs4646287 polymorphisms of NTCP were determined by allelic discrimination using commercial TaqMan probes in blood samples of 1021 Thai individuals. These subjects included 610 patients with chronic HBV infection [CHB, 305 with hepatocellular carcinoma (HCC) and 305 without HCC], 206 subjects with spontaneous HBV clearance and 205 healthy controls who were age and gender-matched. RESULTS: The frequencies of rs2296651 A minor allele in the CHB group, the HBV clearance group and healthy controls were 7.8, 7.3 and 13.9%, respectively. For rs4646287, the frequencies of T minor allele of the corresponding groups were 10.4, 8.0 and 9.5%, respectively. Compared with healthy controls, the frequencies of rs2296651 GA + AA genotypes were significantly lower in the CHB group (P < 0.001) and in the HBV clearance group (P = 0.001). There was no difference in their distribution between the HBV clearance and CHB groups. Among the CHB group, the distribution of GA + AA genotypes in patients with HCC were significantly lower than in patients without HCC (P = 0.014). The frequencies of HBeAg positivity in patients harboring GG and GA + AA genotypes were 39.8 and 23.5%, respectively (P = 0.004). Among patients with HCC, the mean HBV DNA of the corresponding genotypes were 4.9 ± 1.3 vs. 2.7 ± 1.0 log10 IU/mL, respectively (P < 0.001). There was no difference in genotype and allele frequencies of rs4646287 polymorphism among all studied groups. CONCLUSIONS: Our results showed that rs2296651 polymorphism was associated with a decreased risk of susceptibility to HBV infection and the development of HCC. These data suggest that the NTCP polymorphism might have an influence on natural history of HBV infection in Thai individuals. This abstract was partly presented at the American Association for the Study of Liver Diseases (AASLD) Meeting 2018, November 9-13, 2018, in San Francisco, CA, USA and was published in Hepatology 2018; 68:1237A-1238A.


Assuntos
Carcinoma Hepatocelular/genética , Predisposição Genética para Doença/genética , Hepatite B Crônica/genética , Neoplasias Hepáticas/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Polimorfismo de Nucleotídeo Único , Simportadores/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/etnologia , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Hepatite B Crônica/complicações , Hepatite B Crônica/etnologia , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/etnologia , Masculino , Pessoa de Meia-Idade , Tailândia
17.
Oncol Rep ; 42(1): 189-201, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115549

RESUMO

The present study aimed to investigate the clinical significance and prospective molecular mechanism of cystatin (CST) genes in patients with hepatitis B virus (HBV)­related hepatocellular carcinoma (HCC). The role of CST genes in the molecular mechanism of HCC was revealed through bioinformatics analysis. The clinical significance of CST genes was investigated using GSE14520­derived data from patients with HBV­related HCC. Gene set enrichment analysis (GSEA) was used to identify pathways in which the CST genes were enriched, as well as the association between these pathways and HCC. The expression levels of CST1, CST2, CST5, CSTA and CSTB genes were higher in HCC tissue compared with in normal tissue; conversely, CST3 and CST7 were reduced in HCC tissue. Subsequent receiver operating characteristic analysis of the CST genes demonstrated that CST7 and CSTB genes may function as potential diagnostic markers for HCC. Furthermore, the expression levels of CST6 and CST7 were strongly associated with recurrence­free survival and overall survival of patients with HBV­related HCC. GSEA of the CST genes revealed that CST7 was significantly enriched in tumor evasion and tolerogenicity, cancer progenitors, liver cancer late recurrence, liver cancer progression and several liver cancer subclasses. In addition, CST genes demonstrated homology in terms of protein structure and were revealed to be strongly co­expressed. The present findings suggested that CST7 and CSTB genes may serve as potential prognostic and diagnostic biomarkers for HCC.


Assuntos
Carcinoma Hepatocelular/virologia , Cistatinas/genética , Hepatite B Crônica/genética , Neoplasias Hepáticas/virologia , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Masculino , Prognóstico , Mapas de Interação de Proteínas , Análise de Sobrevida , Regulação para Cima
18.
BMC Med Genet ; 20(1): 85, 2019 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-31109299

RESUMO

BACKGROUND: Glycogen storage disease type I (GSD I), also known as von Gierk disease, is a metabolic disorder leading to the excessive accumulation of glycogen and fat in organs, characterized by hepatomegaly, hypoglycemia, lactic acidemia, hyperlipidemia, hyperuricemia, puberty delay and growth retardation, which can be indicated by height, weight, blood glucose and blood lipids. CASE PRESENTATION: Here we present a 16-year-old male patient with GSD Ia complicated with hepatic adenoma and combined with hepatitis B. As a chronic hepatitis B patient, the patient was admitted to hospital in order to further clarify the nature of hepatic space occupancy because of suspicion of hepatocellular carcinoma. However, the imaging studies did not support hepatocellular carcinoma certainly. And by tracing his clinical history, we suggested that he might suffer from GSD I. Finally the diagnosis was confirmed by MRI (Gd-EOB-DTPA), liver biopsy and whole exome sequencing (WES). The WES discovered a homozygous point mutation at the exon 5 of G6PC gene at 17th chromosome, c.G648 T (p.L216 L, NM_000151, rs80356484). This pathogenic mutation causes CTG changing to CTT at protein 216. Though both codons encode leucine, this silent mutation creates a new splicing site 91 bp downstream of the authentic splice site. According to previous research, this mutation is a disease causal variant for GSD Ia, and has a high frequency among GSD patients in China and Japan. This patient was finally diagnosed as GSD Ia complicated with hepatic adenoma and combined with chronic hepatitis B, and received corn starch therapy immediately after GSD was suspected. After receiving corn starch therapy, the height and weight of the patient were increased, and the secondary sexual characteristics were developed, including beard, pubic hair and seminal emission. Unexpectedly, the liver adenomas were still increasing, and we did not find any cause to explain this phenomenon. CONCLUSION: This patient was diagnosed as GSD Ia combined with chronic hepatitis B, who responded to corn starch intervention. For childhood patients with hypoglycaemia, hyperlipidemia, puberty delay and growth retardation, GSD should be considered. Gene sequencing is valuable for the quick identification of GSD subtypes.


Assuntos
Doença de Depósito de Glicogênio Tipo I/genética , Hepatite B Crônica/genética , Adolescente , Feminino , Doença de Depósito de Glicogênio Tipo I/complicações , Doença de Depósito de Glicogênio Tipo I/diagnóstico por imagem , Doença de Depósito de Glicogênio Tipo I/dietoterapia , Humanos , Masculino , Linhagem , Mutação Puntual
19.
PLoS Pathog ; 15(4): e1007742, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31026293

RESUMO

Persistent hepatitis B virus (HBV) infection relies on the establishment and maintenance of covalently closed circular (ccc) DNA, a 3.2 kb episome that serves as a viral transcription template, in the nucleus of an infected hepatocyte. Although evidence suggests that cccDNA is the repair product of nucleocapsid associated relaxed circular (rc) DNA, the cellular DNA polymerases involving in repairing the discontinuity in both strands of rcDNA as well as the underlying mechanism remain to be fully understood. Taking a chemical genetics approach, we found that DNA polymerase alpha (Pol α) is essential for cccDNA intracellular amplification, a genome recycling pathway that maintains a stable cccDNA pool in infected hepatocytes. Specifically, inhibition of Pol α by small molecule inhibitors aphidicolin or CD437 as well as silencing of Pol α expression by siRNA led to suppression of cccDNA amplification in human hepatoma cells. CRISPR-Cas9 knock-in of a CD437-resistant mutation into Pol α genes completely abolished the effect of CD437 on cccDNA formation, indicating that CD437 directly targets Pol α to disrupt cccDNA biosynthesis. Mechanistically, Pol α is recruited to HBV rcDNA and required for the generation of minus strand covalently closed circular rcDNA, suggesting that Pol α is involved in the repair of the minus strand DNA nick in cccDNA synthesis. Our study thus reveals that the distinct host DNA polymerases are hijacked by HBV to support the biosynthesis of cccDNA from intracellular amplification pathway compared to that from de novo viral infection, which requires Pol κ and Pol λ.


Assuntos
DNA Polimerase I/metabolismo , DNA Circular/genética , DNA Viral/genética , Vírus da Hepatite B/genética , Hepatite B Crônica/genética , Replicação Viral/genética , DNA Circular/metabolismo , DNA Viral/metabolismo , Células Hep G2 , Vírus da Hepatite B/metabolismo , Hepatite B Crônica/metabolismo , Hepatite B Crônica/virologia , Hepatócitos/metabolismo , Hepatócitos/virologia , Humanos , Vírion
20.
Asian Pac J Cancer Prev ; 20(4): 1257-1264, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31030503

RESUMO

Background: Vitamin D deficiency is related to poor clinical outcomes in patients with chronic hepatitis B virus (HBV) infection. Methods: We aimed to investigate the association between the genetic variants in the vitamin D metabolic pathway and the response to pegylated interferon (Peg-IFN) therapy in patients with HBeAg-negative chronic HBV infection. One hundred seven patients treated with Peg-IFN for 48 weeks were selected from 13 specialty hospitals. Eight genotypes of vitamin D cascade genes, including CYP27B1 (rs10877012), DHCR7 (rs12785878), CYP2R1 (rs2060793, rs12794714) and GC (rs4588, rs7041, rs222020, rs2282679), were found. Results: Eighty-two patients (83.7%) were infected with HBV genotype C. Eight patients had compensated liver cirrhosis (8.7%). At 24 weeks after treatment discontinuation, 41 patients (42.3%) achieved sustained treatment response, 53 (55.2%) obtained HBV DNA<2,000 IU/ml, 6 (5.6%) gained HBsAg seroclearance, 2 (1.9%) had HBsAg seroconversion and 69 (64.5%) exhibited alanine aminotransferase (ALT) normalization. Multivariate analysis revealed that baseline HBsAg level (OR =0.06, 95% CI: 0.08-0.49, p=0.008) and the GC rs222020 TT genotype (OR=17.72, 95% CI: 1.07-294.38, p=0.04) independently predicted sustained HBsAg seroclearance. In addition, this genotype was a predictor for normalization of ALT (OR=4.61, 95%CI: 1.59-13.40, p=0.005) after therapy. The HBsAg levels at baseline and during and post-treatment tended to be reduced with the GC rs222020 TT compared with the non-TT genotypes. The other studied polymorphisms were not associated with treatment response. Conclusions: The GC rs222020 TT genotype, which is a variant in the vitamin D-binding protein gene, could identify HBeAg-negative patients who have a high probability to achieve HBsAg clearance and ALT normalization after treatment with Peg-IFN.


Assuntos
Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/imunologia , Hepatite B Crônica/sangue , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Polimorfismo Genético , Proteína de Ligação a Vitamina D/genética , Antivirais/uso terapêutico , Feminino , Seguimentos , Antígenos E da Hepatite B/imunologia , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/genética , Hepatite B Crônica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Soroconversão
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