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1.  A Novel Variant Marking HLA-DP Expression Levels Predicts Recovery from Hepatitis B Virus Infection 
Journal of Virology  2012;86(12):6979-6985.
Variants near the HLA-DP gene show the strongest genome-wide association with chronic hepatitis B virus (HBV) infection and HBV recovery/persistence in Asians. To test the effect of the HLA-DP region on outcomes to HBV infection, we sequenced the polymorphic HLA-DPB1 and DPA1 coding exons and the corresponding 3′ untranslated regions (3′UTRs) in 662 individuals of European-American and African-American ancestry. The genome-wide association study (GWAS) variant (rs9277535; 550A/G) in the 3′UTR of the HLA-DPB1 gene that associated most significantly with chronic hepatitis B and outcomes to HBV infection in Asians had a marginal effect on HBV recovery in our European- and African-American samples (odds ratio [OR] = 0.39, P = 0.01, combined ethnic groups). However, we identified a novel variant in the HLA-DPB1 3′UTR region, 496A/G (rs9277534), which associated very significantly with HBV recovery in both European and African-American populations (OR = 0.37, P = 0.0001, combined ethnic groups). The 496A/G variant distinguishes the most protective HLA-DPB1 allele (DPB1*04:01) from the most susceptible (DPB1*01:01), whereas 550A/G does not. 496A/G has a stronger effect than any individual HLA-DPB1 or DPA1 allele and any other HLA alleles that showed an association with HBV recovery in our European-American cohort. The 496GG genotype, which confers recessive susceptibility to HBV persistence, also associates in a recessive manner with significantly higher levels of HLA-DP surface protein and transcript level expression in healthy donors, suggesting that differences in expression of HLA-DP may increase the risk of persistent HBV infection.
doi:10.1128/JVI.00406-12
PMCID: PMC3393572  PMID: 22496224
2.  Tripartite Motif-Containing 22 Gene -364T/C Polymorphism Associated With Hepatitis B Virus Infection in Chinese Han Population 
Hepatitis Monthly  2014;14(1):e12110.
Background:
Hepatitis B virus (HBV) infection significantly contributes to the onset of liver disease and hepatocellular carcinoma. Understanding the pathogenesis of HBV infection susceptibility could help us to control HBV infection effectively.
Objectives:
This study investigated single nucleotide polymorphisms (SNPs) of the tripartite motif-containing 22 (TRIM22) gene associated with HBV infection outcome.
Patients and Methods:
A total of 765 Chinese Han subjects were enrolled: 293 patients were presented with chronic hepatitis B (CHB), 224 were asymptomatic HBV carriers, 248 had self-limited HBV infection, and all of them were recruited for TRIM22 SNPs genotyping. RING and SPRY domains of TRIM22 gene were DNA-sequenced, and HBV serum markers and HBV DNA were measured quantitatively in all subjects.
Results:
243 (31.76%) of 765 Chinese Han patients showed genetic variation in the TRIM22 gene. TRIM22 SNPs were mainly in RING area -364T/C site, accounting for 98.35% of the population. There were no significant differences (P > 0.05) in the RING domain -364T/C SNP and allele frequencies between patients with chronic hepatitis and asymptomatic HBV carriers. The CC genotype of TRIM22 gene RING domain -364T/C locus (rs10838543) was associated with chronic HBV infection (OR = 2.30, 95% CI = 1.24-3.97, P = 0.0012; OR = 2.26, 95% CI = 1.08-3.74, P = 0.002) and a mutant allele C carrier of the TRIM22 gene was associated with HBV chronic infection (OR = 1.97, 95% CI = 1.10-3.75, P = 0.0049; OR = 2.12, 95% CI = 1.17-3.89, P = 0.0038).
Conclusions:
TRIM22 gene RING domain -364T/C polymorphism is associated with chronic HBV infection in Chinese Han population.
doi:10.5812/hepatmon.12110
PMCID: PMC3929861  PMID: 24596578
Hepatitis B virus; TRIM22 Protein, Human; Polymorphism, Single Nucleotide
3.  Association of T-Cell Immunoglobulin and Mucin Domain-Containing Molecule 3 (Tim-3) Polymorphisms with Susceptibility and Disease Progression of HBV Infection 
PLoS ONE  2014;9(5):e98280.
Purpose
T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) plays an important role in regulating T cells in hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). However, few researches have reported the association of Tim-3 genetic variants with susceptibility and progression of HBV infection. In this study, we focused on the association of Tim-3 polymorphisms with HBV infection, HBsAg seroclearance and hepatocellular carcinoma.
Methods
A total of 800 subjects were involved in this study. Four groups were studied here, including HBV, HBsAg seroclearance, HBV-associated HCC and healthy controls. Three single-nucleotide polymorphisms (SNPs) of Tim-3, rs246871, rs25855 and rs31223 were genotyped to analyze the association of Tim-3 polymorphisms with susceptibility and disease progression of HBV infection.
Results
Our study found that rs31223 and rs246871 were associated with disease progression of HBV infection, while none of the three SNPs was relevant to HBV susceptibility. The minor allele “C” of rs31223 was found to be associated with an increased probability of HBsAg seroclearance (P = 0.033) and genotype “CC” of rs246871 to be associated with an increased probability of HBV-associated HCC (P = 0.007). In accordance, haplotypic analysis of the three polymorphisms also showed that the haplotype block CGC* and TGC* were significantly associated with HBsAg seroclearance (P<0.05) while haplotype block CAT*, CGT*, TAC* and TGT* were significantly associated with HBV-associated HCC (all P<0.05).
Conclusions
Genetic variants of Tim-3 have an important impact on disease progression of HBV infection. With specific Tim-3 polymorphisms, patients infected with HBV could be potential candidates of HCC and HBsAg seroclearance.
doi:10.1371/journal.pone.0098280
PMCID: PMC4035322  PMID: 24867713
4.  Polymorphisms in CISH Gene Are Associated with Persistent Hepatitis B Virus Infection in Han Chinese Population 
PLoS ONE  2014;9(6):e100826.
Background and Aim
Cytokine-inducible SRC homology 2 domain protein (CISH) is the first member of the suppressors of cytokine signaling (SOCS) protein family. An association between multiple CISH polymorphisms and susceptibility to infectious diseases has been reported. This study aimed to investigate the possible association of these single nucleotide polymorphisms (SNPs) in CISH gene with different outcomes of Hepatitis B virus (HBV) infection.
Methods
1019 unrelated Chinese Han subjects, including 240 persistent asymptomatic HBV carriers, 217 chronic hepatitis B patients, 137 HBV-related liver cirrhosis patients, and 425 cases of spontaneously recovered HBV as controls, were studied. Four SNPs (rs622502, rs2239751, rs414171 and rs6768300) in CISH gene were genotyped with the snapshot technique. Transcriptional activity of the CISH promoter was assayed in vitro using the dual-luciferase reporter assay system.
Results
At position rs414171, A allele and AA genotype frequencies were significantly higher in the HBV-resolved group as compared to the persistent HBV infection group. At position rs2239751, TT genotype was further observed in the HBV-resolved group. Using asymptomatic HBV carriers as controls, our results indicated that the rs414171 and rs2239751 polymorphisms were unrelated to HBV progression. The other two SNPs (rs622502 and rs6768300) showed no association with persistent HBV infection. Haplotype analysis revealed that the GGCA haplotype was associated with spontaneous clearance of HBV in this population. Moreover, luciferase activity was significantly higher in the PGL3-Basic-rs414171T construct as compared to the PGL3-Basic-rs414171A construct (p<0.001).
Conclusion
Two SNPs (rs414171 and rs2239751) in the CISH gene were associated with persistent HBV infection in Han Chinese population, but not with HBV progression.
doi:10.1371/journal.pone.0100826
PMCID: PMC4071005  PMID: 24964072
5.  Hepatitis B virus and hepatocellular carcinoma at the miRNA level 
AIM: To study Hepatitis B virus (HBV) infection and its association with hepatocellular carcinoma (HCC) at the miRNA level.
METHODS: Three cellular models were used to investigate miRNA expression changes during HBV infection: human HepG2 hepatoblastoma cell line as a model without HBV infection; HepG2 cell line transfected with a 1.3-fold full-length HBV genome as an acute infection model; and HepG2.2.15 cell line, which is derived from HepG2 and stably transfected with a complete HBV genome, as a chronic infection model. The miRNA levels were examined using microarray technology. To explore the relationship between HBV infection and HCC genesis at the miRNA level, we downloaded from national center for biotechnology information Gene Expression Omnibus an miRNA expression dataset derived from HCC patients, most of whom are HBV carriers. We compared the miRNA expression alterations during HBV infection with those in HCC patients, by analyzing miRNA expression change profiles statistically.
RESULTS: Seventy-seven and 48 miRNAs were differentially expressed during acute and chronic HBV infection, respectively. Among these miRNAs, 25 were in common, the intersection of which was significant under the hypergeometric test (P = 1.3 × 10-11). Fourteen miRNAs were observed to change coherently in the acute and chronic infections, with one upregulated and 13 downregulated. Eleven showed inverse changes during the two phases of infection; downregulated in the acute infection and upregulated in the chronic infection. The results imply that common and specific mechanisms exist at the miRNA level during acute and chronic HBV infection. Besides, comparative analysis of the miRNA expression changes during HBV infection with those in HCC indicates that, although miRNA expression changes during HBV infection are distinct from those in HCC patients (P < 2.2 × 10-16), they exhibited significant correlations (P = 0.0229 for acute infection; P = 0.0084 for chronic infection). Perturbation of miRNA expression during chronic HBV infection was closer to that in HCC patients than that during acute HBV infection. This observation implies the contribution of miRNAs to HCC genesis from HBV infection. According to their patterns of differential expression in acute and chronic HBV infection, as well as in HCC, miRNAs of potential research interest could be identified, such as miR-18a/miR-18b, miR-106a, miR-221 and miR-101. For instance, the gradient expression alteration of miR-221 in the above three phases, which is downregulated in acute HBV infection, normally expressed in chronic HBV infection, and upregulated in HCC, indicates that it may be a key effector for progression of the disease.
CONCLUSION: Our analysis provides insights into HBV infection and related HCC in relation to miRNAs, and reveals some candidate miRNAs for future studies.
doi:10.3748/wjg.v17.i28.3353
PMCID: PMC3160541  PMID: 21876625
Hepatitis B virus; Hepatocellular carcinoma; MiRNA
6.  GWAS Identifies Novel Susceptibility Loci on 6p21.32 and 21q21.3 for Hepatocellular Carcinoma in Chronic Hepatitis B Virus Carriers 
PLoS Genetics  2012;8(7):e1002791.
Genome-wide association studies (GWAS) have recently identified KIF1B as susceptibility locus for hepatitis B virus (HBV)–related hepatocellular carcinoma (HCC). To further identify novel susceptibility loci associated with HBV–related HCC and replicate the previously reported association, we performed a large three-stage GWAS in the Han Chinese population. 523,663 autosomal SNPs in 1,538 HBV–positive HCC patients and 1,465 chronic HBV carriers were genotyped for the discovery stage. Top candidate SNPs were genotyped in the initial validation samples of 2,112 HBV–positive HCC cases and 2,208 HBV carriers and then in the second validation samples of 1,021 cases and 1,491 HBV carriers. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 (OR = 1.30, P = 1.13×10−19) and rs455804 (GRIK1) on 21q21.3 (OR = 0.84, P = 1.86×10−8), which were further replicated in the fourth independent sample of 1,298 cases and 1,026 controls (rs9272105: OR = 1.25, P = 1.71×10−4; rs455804: OR = 0.84, P = 6.92×10−3). We also revealed the associations of HLA-DRB1*0405 and 0901*0602, which could partially account for the association at rs9272105. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV–related HCC, suggesting the involvement of glutamate signaling in the development of HBV–related HCC.
Author Summary
Previous studies strongly suggest the importance of genetic susceptibility for hepatocellular carcinoma (HCC). However, the studies about genetic etiology on HBV–related HCC were limited. Our genome-wide association study included 523,663 autosomal SNPs in 1,538 HBV–positive HCC patients and 1,465 chronic HBV carriers for the discovery analysis. 2,112 HBV–positive HCC cases and 2,208 HBV carriers (the initial validation), and 1,021 cases and 1,491 HBV carriers (the second validation), were then analyzed for validation. The fourth independent samples of 1,298 cases and 1,026 controls were analyzed as replication. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 and rs455804 (GRIK1) on 21q21.3. HLA-DRB1 molecules play an important role in chronic HBV infection and progression to HCC. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV–related HCC, suggesting the involvement of glutamate signaling in the development of HBV–related HCC.
doi:10.1371/journal.pgen.1002791
PMCID: PMC3395595  PMID: 22807686
7.  Leukocyte Telomere Length-Related rs621559 and rs398652 Genetic Variants Influence Risk of HBV-Related Hepatocellular Carcinoma 
PLoS ONE  2014;9(11):e110863.
Recent genome-wide association studies (GWAS) have identified eleven leukocyte telomere length (LTL)-related single nucleotide polymorphisms (SNPs). Since LTL has been associated with risk of many malignancies, LTL-related SNPs may contribute to cancer susceptibility. To test this hypothesis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we genotyped these eleven LTL-related SNPs in a case-control set including 1186 HBV-related HCC cases, 508 chronic HBV carriers and 1308 healthy controls at the discovery stage. The associations of HCC risk with these SNPs were further confirmed in an independent case-control set. We found that 1p34.2 rs621559 and 14q21 rs398652 were significantly associated with HBV-related HCC risk (both P<0.005 after Bonferroni corrections). There was no significant difference of either rs621559 or rs398652 genotypes between chronic HBV carriers and healthy controls, demonstrating that the association was not due to predisposition to HBV infection. In the pooled analyses (1806 HBV-related HCC cases and 1954 controls), we observed a decreased HCC risk, 0.72-times, associated with the 1p34.2 rs621559 AA genotype compared to the GG genotype (P = 1.6×10−6). Additionally, there was an increased HCC risk, 1.27-fold, associated with the rs398652 GG genotype (P = 3.3×10−6). A statistical joint effect between the rs621559 GG and rs398652 GG genotypes may exist in elevating risk of HBV-related HCC. We show, for the first time, that rs398652 and rs621559 might be marker genetic variants for risk of HBV-related HCC in the Chinese population.
doi:10.1371/journal.pone.0110863
PMCID: PMC4218833  PMID: 25365256
8.  Strong Influence of HLA-DP Gene Variants on Development of Persistent Chronic HBV Carriers in the Han Chinese Population 
Hepatology (Baltimore, Md.)  2011;53(2):422-428.
Chronic hepatitis B virus (HBV) infection is a major health issue, especially in Asia. A recent genome-wide association study (GWAS) has implicated genetic variants in the HLA-DP locus associated with chronic hepatitis B in Japanese and Thai populations. To confirm whether the polymorphisms at the HLA-DP genes are associated with persistent chronic hepatitis B virus infection in Han Chinese, we conducted an independent case-control study using 521 persistent chronic HBV carriers and 819 controls that included 571 persons with HBV natural clearance and 248 never HBV-infected (healthy) individuals. Eleven single nucleotide polymorphisms (SNPs) in a region including HLA-DPA and HLA-DPB and an adjacent SNP in strong linkage disequilibrium (LD) with a neighboring HLA-DR13 locus were genotyped using TaqMan SNP genotyping assay. Eleven variants at HLA-DP showed a strong association with persistent chronic HBV carrier status (p = 1.82×10−12 to 0.01). We also stratified the analysis by HBV clearance status to test the association between these polymorphisms and HBV natural clearance; similar results were obtained (p = 2.70×10−11 to 0.003). Included SNPs define highly structured haplotypes which were also strongly associated with HBV chronic infection (Block 1: odds ratio (OR) = 0.54, p = 8.73×10−7; block 2: OR = 1.98, p = 1.37×10−10). These results further confirm that genetic variants in the HLA-DP locus are strongly associated with persistent HBV infection in the Han Chinese population.
doi:10.1002/hep.24048
PMCID: PMC3056070  PMID: 21274863
Chronic hepatitis B; Haplotype association; GWAS; SNPs; Joint effects
9.  Novel Hepatitis B Virus Genotype A Subtyping Assay That Distinguishes Subtype Aa from Ae and Its Application in Epidemiological Studies 
Journal of Virology  2004;78(14):7575-7581.
The eight genotypes of hepatitis B virus (HBV) have different geographical distributions, virological characteristics, and clinical manifestations. A unique subtype of HBV genotype A (HBV/A) was reported in sub-Saharan Africa, raising the possibility that patients infected with this subtype (HBV/Aa [“a” for African and Asian]) may have different clinical outcomes than other HBV/A isolates (HBV/Ae [“e” for European]). Comparison between 30 HBV/Aa and 30 HBV/Ae isolates indicated that almost all HBV/Ae isolates had G at nucleotide (nt) 1809 and C at nt 1812, whereas HBV/Aa isolates had T1809/T1812. Taking advantage of these two single nucleotide polymorphisms (SNPs), a novel subtype-specific PCR assay in the X/precore/core region was developed. This assay was combined with a restriction fragment length polymorphism assay using BglII in a different region (nt 1984 to 1989), which has a SNP distinguishing HBV/Aa from HBV/Ae, resulting in 100% specificity for the combined assay. Application of the subtyping assay using sera from 109 paid donors in the United States indicated significantly different distributions of HBV/A subtypes among races; African-Americans, Caucasians, and Hispanics had HBV/Ae, whereas Asians had mainly HBV/Aa, suggesting that the HBV/Aa isolates may have been imported by recent immigration from Asia. In conclusion, the specificity and sensitivity of the combined subtyping assay were confirmed, and its usefulness was demonstrated in a practical context.
doi:10.1128/JVI.78.14.7575-7581.2004
PMCID: PMC434120  PMID: 15220432
10.  New Susceptibility and Resistance HLA-DP Alleles to HBV-Related Diseases Identified by a Trans-Ethnic Association Study in Asia 
PLoS ONE  2014;9(2):e86449.
Previous studies have revealed the association between SNPs located on human leukocyte antigen (HLA) class II genes, including HLA-DP and HLA-DQ, and chronic hepatitis B virus (HBV) infection, mainly in Asian populations. HLA-DP alleles or haplotypes associated with chronic HBV infection or disease progression have not been fully identified in Asian populations. We performed trans-ethnic association analyses of HLA-DPA1, HLA-DPB1 alleles and haplotypes with hepatitis B virus infection and disease progression among Asian populations comprising Japanese, Korean, Hong Kong, and Thai subjects. To assess the association between HLA-DP and chronic HBV infection and disease progression, we conducted high-resolution (4-digit) HLA-DPA1 and HLA-DPB1 genotyping in a total of 3,167 samples, including HBV patients, HBV-resolved individuals and healthy controls. Trans-ethnic association analyses among Asian populations identified a new risk allele HLA-DPB1*09∶01 (P = 1.36×10−6; OR = 1.97; 95% CI, 1.50–2.59) and a new protective allele DPB1*02∶01 (P = 5.22×10−6; OR = 0.68; 95% CI, 0.58–0.81) to chronic HBV infection, in addition to the previously reported alleles. Moreover, DPB1*02∶01 was also associated with a decreased risk of disease progression in chronic HBV patients among Asian populations (P = 1.55×10−7; OR = 0.50; 95% CI, 0.39–0.65). Trans-ethnic association analyses identified Asian-specific associations of HLA-DP alleles and haplotypes with HBV infection or disease progression. The present findings will serve as a base for future functional studies of HLA-DP molecules in order to understand the pathogenesis of HBV infection and the development of hepatocellular carcinoma.
doi:10.1371/journal.pone.0086449
PMCID: PMC3919706  PMID: 24520320
11.  A population-based study to investigate host genetic factors associated with hepatitis B infection and pathogenesis in the Chinese population 
Background
Hepatitis B virus (HBV) infection is a significant public health problem that may lead to chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Approximately 30% of the world's population has been infected with HBV and approximately 350 million (5–6%) are persistent carriers. More than 120 million Chinese are infected with HBV. The role of host genetic factors and their interactions with environmental factors leading to chronic HBV infection and its complications are not well understood. We believe that a better understanding of these factors and interactions will lead to more effective diagnostic and therapeutic options.
Methods/Design
This is a population-based, case-control study protocol to enroll 2200 Han Chinese from medical centers in northern and western China. Adult subjects in the following groups are being enrolled: healthy donors (n = 200), HBV infected persons achieving virus clearance (n = 400), asymptomatic HBV persistent carriers (n = 400), chronic hepatitis B cases (n = 400), decompensated liver cirrhosis with HBV infection cases (n = 400), and hepatocellular carcinoma with HBV infection cases (n = 400). In addition, for haplotype inference and quality control of sample handling and genotyping results, children of 1000 cases will be asked to provide a buccal sample for DNA extraction. With the exception of adult patients presenting with liver cirrhosis or HCC, all other cases and controls will be 40 years or older at enrollment. A questionnaire is being administered to capture dietary and environmental risk factors. Both candidate-gene and genome-wide association approaches will be used to assess the role of single genetic factors and higher order interactions with other genetic or environmental factors in HBV diseases.
Conclusion
This study is designed and powered to detect single gene effects as well as gene-gene and environmental-gene interactions. The identification of allelic polymorphisms in genes involved in the pathway leading to chronic viral infection, liver cirrhosis and, ultimately, hepatocellular carcinoma would provide insights to those factors leading to HBV replication, liver inflammation, fibrosis, and the carcinogenic process. An understanding of the contribution of host genetic factors and their interactions may inform public health policy, improve diagnostics and clinical management, and provide targets for drug development.
doi:10.1186/1471-2334-8-1
PMCID: PMC2238742  PMID: 18171470
12.  Association between IL28B Polymorphisms and Spontaneous Clearance of Hepatitis B Virus Infection 
PLoS ONE  2013;8(7):e69166.
Background/Aims
Single-nucleotide polymorphisms (SNPs) near the interleukin 28B gene (IL28B; interferon [IFN]-λ-3) are associated with outcomes of chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infection treated with peginterferon (PEG-IFN) alpha-based antiviral therapy. In this study, we investigated the influence of IL28B polymorphisms on spontaneous clearance of HBV infection in a large Korean cohort.
Methods
Between January 2007 and June 2010, a total of 208 patients with chronic HBV infection and newly diagnosed HBV-related hepatocellular carcinoma were recruited as the CC group [HBsAg(+) for >6 months, anti-HBc(+), and anti-HBs(-)]. In addition, 351 organ donors were stratified into the UE group [n = 106; HBsAg(-), anti-HBc(-), and anti-HBs(-)] or the SC group [n = 245; HBsAg(-), anti-HBc(+), and anti-HBs(+)]. The SNaPshot ddNTP Primer Extension Kit (Applied Biosystems, Foster City, CA) was used for SNP detection. Direct full sequencing of the IL28B coding region was attempted.
Results
Regardless of group, rs12979860 CC was most frequently identified (85.0% in UE, 85.9% in SC, and 93.5% in CC, respectively), whereas rs12979860 TT was not identified in any group. Similarly, rs12980275 AA and rs8099917 TT were most frequently identified (≥85%) regardless of group, whereas rs12980275 GG was identified in only one subject in the SC group. In addition, rs8099917 GG was not identified. The prevalences of CC in rs12979860, AA in rs12980275, and TT in rs8099917 were significantly higher in the CC group when compared with the UE and SC group (all P<0.05). Among 19 novel SNPs in the IL28B coding region, the proportions of 6 SNPs were significantly different among the UE, SC, and CC groups (all P<0.05).
Conclusions
The SNP upstream of IL28B that has the strongest genetic association with HCV recovery has an inverse influence on HBV recovery. Additional studies are needed to understand the mechanisms of this SNP in HBV infection.
doi:10.1371/journal.pone.0069166
PMCID: PMC3714234  PMID: 23874902
13.  Association between HLA Variations and Chronic Hepatitis B Virus Infection in Saudi Arabian Patients 
PLoS ONE  2014;9(1):e80445.
Hepatitis B virus (HBV) infection is a leading cause of liver diseases including cirrhosis and hepatocellular carcinoma. Human leukocyte antigens (HLAs) play an important role in the regulation of immune response against infectious organisms, including HBV. Recently, several genome-wide association (GWAS) studies have shown that genetic variations in HLA genes influence disease progression in HBV infection. The aim of this study was to investigate the role of HLA genetic polymorphisms and their possible role in HBV infection in Saudi Arabian patients. Variations in HLA genes were screened in 1672 subjects who were divided according to their clinical status into six categories as follows; clearance group, inactive carriers, active carriers, cirrhosis, hepatocellular carcinoma (HCC) patients and uninfected healthy controls. Three single nucleotide polymorphisms (SNPs) belonged to HLA-DQ region (rs2856718, rs7453920 and rs9275572) and two SNPs belonged to HLA-DP (rs3077 and rs9277535) were studied. The SNPs were genotyped by PCR-based DNA sequencing (rs2856718) and allele specific TaqMan genotyping assays (rs3077, rs7453920, rs9277535 and rs9275572). The results showed that rs2856718, rs3077, rs9277535 and rs9275572 were associated with HBV infection (p = 0.0003, OR = 1.351, CI = 1.147–1.591; p = 0.041, OR = 1.20, CI = 1.007–1.43; p = 0.045, OR = 1.198, CI = 1.004–1.43 and p = 0.0018, OR = 0.776, CI = 0.662–0.910, respectively). However, allele frequency of rs2856718, rs7453920 and rs9275572 were found more in chronically infected patients when compared to clearance group infection (p = 0.0001, OR = 1.462, CI = 1.204–1.776; p = 0.0178, OR = 1.267, CI = 1.042–1.540 and p = 0.010, OR = 0.776, CI = 0.639–0.942, respectively). No association was found when polymorphisms in HLA genes were compared in active carriers versus cirrhosis/HCC patients. In conclusion, these results suggest that variations in HLA genes could affect susceptibility to and clearance of HBV infection in Saudi Arabian patients.
doi:10.1371/journal.pone.0080445
PMCID: PMC3898905  PMID: 24465366
14.  HLA class II associated with outcomes of hepatitis B and C infections 
Several factors influence the clinical course of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. The human leukocyte antigen (HLA) system, the major histocompatibility complex (MHC) in humans, has been considered one of the most important host factors with respect to outcomes. To date, conventional genotyping studies have shown that HLA class II loci are mainly associated with spontaneous clearance of HBV and HCV. However, the specific HLA locus associated with the outcomes of hepatitis virus infection remains unclear. A recent genome-wide association study (GWAS) using a comprehensive approach for human genotyping demonstrated single nucleotide polymorphisms (SNPs) associated with the outcomes of hepatitis virus infection. Examination of large numbers of cohorts revealed that several SNPs in both HLA-DPA1 and HLA-DPB1 loci are associated with persistent HBV infection in Asian populations. To date, however, few studies have focused on HLA-DP because polymorphisms of HLA-DP haplotype do not vary greatly as compared with other loci of HLA. There are not enough studies to reveal the function of HLA-DP. GWAS additionally detected candidate SNPs within HLA loci associated with chronic HBV or HCV hepatitis, hepatic fibrosis, and the development of hepatocellular carcinoma. The results of one cohort were not always consistent with those of other cohorts. To solve several controversial issues, it is necessary to validate reported SNPs on HLA loci in global populations and to elucidate the HLA-allele-regulated molecular response to hepatitis virus infection.
doi:10.3748/wjg.v19.i33.5395
PMCID: PMC3761092  PMID: 24023482
Hepatitis B virus; Hepatitis C virus; Hepatocarcinogenesis; Human leukocyte antigen; Genome-wide association studies; Genotyping; Persistent infection
15.  Hepatitis B Virus Disrupts Mitochondrial Dynamics: Induces Fission and Mitophagy to Attenuate Apoptosis 
PLoS Pathogens  2013;9(12):e1003722.
Human hepatitis B virus (HBV) causes chronic hepatitis and is associated with the development of hepatocellular carcinoma. HBV infection alters mitochondrial metabolism. The selective removal of damaged mitochondria is essential for the maintenance of mitochondrial and cellular homeostasis. Here, we report that HBV shifts the balance of mitochondrial dynamics toward fission and mitophagy to attenuate the virus-induced apoptosis. HBV induced perinuclear clustering of mitochondria and triggered mitochondrial translocation of the dynamin-related protein (Drp1) by stimulating its phosphorylation at Ser616, leading to mitochondrial fission. HBV also stimulated the gene expression of Parkin, PINK1, and LC3B and induced Parkin recruitment to the mitochondria. Upon translocation to mitochondria, Parkin, an E3 ubiquitin ligase, underwent self-ubiquitination and facilitated the ubiquitination and degradation of its substrate Mitofusin 2 (Mfn2), a mediator of mitochondrial fusion. In addition to conventional immunofluorescence, a sensitive dual fluorescence reporter expressing mito-mRFP-EGFP fused in-frame to a mitochondrial targeting sequence was employed to observe the completion of the mitophagic process by delivery of the engulfed mitochondria to lysosomes for degradation. Furthermore, we demonstrate that viral HBx protein plays a central role in promoting aberrant mitochondrial dynamics either when expressed alone or in the context of viral genome. Perturbing mitophagy by silencing Parkin led to enhanced apoptotic signaling, suggesting that HBV-induced mitochondrial fission and mitophagy promote cell survival and possibly viral persistence. Altered mitochondrial dynamics associated with HBV infection may contribute to mitochondrial injury and liver disease pathogenesis.
Author Summary
Hepatitis B virus (HBV) chronic infections represent the common cause for the development of hepatocellular carcinoma. Mitochondrial liver injury has been long recognized as one of the consequences of HBV infection during chronic hepatitis. Mitochondria are dynamic organelles that undergo fission, fusion, and selective-autophagic removal (mitophagy), in their pursuit to maintain mitochondrial homeostasis and meet cellular energy requirements. The clearance of damaged mitochondria is essential for the maintenance of mitochondrial and cellular homeostasis. We observed that HBV and its encoded HBx protein promoted mitochondrial fragmentation (fission) and mitophagy. HBV/HBx induced the expression and Ser616 phosphorylation of dynamin-related protein 1 (Drp1) and its subsequent translocation to the mitochondria, resulting in enhanced mitochondrial fragmentation. HBV also promoted the mitochondrial translocation of Parkin, a cytosolic E3 ubiquitin ligase, and subsequent mitophagy. Perturbation of mitophagy in HBV-infected cells resulted in enhanced mitochondrial apoptotic signaling. This shift of the mitochondrial dynamics towards enhanced fission and mitophagy is essential for the clearance of damaged mitochondria and serves to prevent apoptotic cell death of HBV-infected cells to facilitate persistent infection.
doi:10.1371/journal.ppat.1003722
PMCID: PMC3855539  PMID: 24339771
16.  A Common HLA-DPA1 Variant Is Associated with Hepatitis B Virus Infection but Fails to Distinguish Active from Inactive Caucasian Carriers 
PLoS ONE  2012;7(3):e32605.
Background and Aims
Chronic infection with the hepatitis B virus (HBV) is a major health issue worldwide. Recently, single nucleotide polymorphisms (SNPs) within the human leukocyte antigen (HLA)-DP locus were identified to be associated with HBV infection in Asian populations. Most significant associations were observed for the A alleles of HLA-DPA1 rs3077 and HLA-DPB1 rs9277535, which conferred a decreased risk for HBV infection. We assessed the implications of these variants for HBV infection in Caucasians.
Methods
Two HLA-DP gene variants (rs3077 and rs9277535) were analyzed for associations with persistent HBV infection and with different clinical outcomes, i.e., inactive HBsAg carrier status versus progressive chronic HBV (CHB) infection in Caucasian patients (n = 201) and HBsAg negative controls (n = 235).
Results
The HLA-DPA1 rs3077 C allele was significantly associated with HBV infection (odds ratio, OR = 5.1, 95% confidence interval, CI: 1.9–13.7; p = 0.00093). However, no significant association was seen for rs3077 with progressive CHB infection versus inactive HBsAg carrier status (OR = 2.7, 95% CI: 0.6–11.1; p = 0.31). In contrast, HLA-DPB1 rs9277535 was not associated with HBV infection in Caucasians (OR = 0.8, 95% CI: 0.4–1.9; p = 1).
Conclusions
A highly significant association of HLA-DPA1 rs3077 with HBV infection was observed in Caucasians. However, as a differentiation between different clinical courses of HBV infection was not possible, knowledge of the HLA-DPA1 genotype cannot be translated into personalized anti-HBV therapy approaches.
doi:10.1371/journal.pone.0032605
PMCID: PMC3308944  PMID: 22448225
17.  The Influence of Human Leukocyte Antigen and IL-10 Gene Polymorphisms on Hepatitis B Virus Outcome 
Hepatitis Monthly  2012;12(5):320-325.
Context
The clinical outcome of hepatitis B virus (HBV) infection is variable, ranging from spontaneous recovery to an inactive carrier state, chronic hepatitis, occult HBV infection, liver cirrhosis, or hepatocellular carcinoma.
Evidence Acquisition
This variable pattern and clinical outcomes of the infection were mainly determined by virological and host genetic factors. Since the most of host genetic factors associated with HBV infection have currently focused on human leukocyte antigen (HLA) associations and interleukin (IL)-10 gene polymorphisms, this review focuses on the recent progresses in these issues to provide prognostic markers for the outcome of HBV infection.
Results
A study on serum levels of IL-10 in occult HBV infected patients reported that the higher level of IL-10 production may suppress function of the immune system against HBV in patients with occult HBV infection. IL-10 promoter polymorphism at position -592 is associated with susceptibility to occult HBV infection.
Conclusions
Findings of this study suggest that the host HLA polymorphism is an important factor in determining outcome of HBV infection but regarding IL-10 gene promoter polymorphisms, we are still have a long way to achieve a definite conclusion.
doi:10.5812/hepatmon.6094
PMCID: PMC3389357  PMID: 22783343
Hepatitis B Virus; Interleukin (IL)-10 gene; HLA Antigens
18.  Role of HLA-DP Polymorphisms on Chronicity and Disease Activity of Hepatitis B Infection in Southern Chinese 
PLoS ONE  2013;8(6):e66920.
Background and Aims
The association between HLA-DP single nucleotide polymorphisms (SNPs) and chronic hepatitis B virus (HBV) infection varies between different populations. We aimed to study the association between HLA-DP SNPs and HBV infection and disease activity in the Chinese population of Hong Kong.
Methods
We genotyped SNPs rs3077 (near HLA-DPA1) and rs9277378 and rs3128917 (both near HLA-DPB1) in 500 HBV carriers (hepatitis B surface antigen [HBsAg]-positive), 245 non-HBV infected controls (HBsAg- and antibody to hepatitis B core protein [anti-HBc]-negative), and 259 subjects with natural HBV clearance (HBsAg-negative, anti-HBc-positive). Inactive HBV carriers state was defined by HBV DNA levels <2,000 IU/ml and persistently normal alanine aminotransferase level for least 12 months.
Results
Compared to the non-HBV infected subjects, the HBV carriers had a significantly lower frequency of the rs3077 T allele (p = 0.0040), rs9277378 A allele (p = 0.0068) and a trend for lower frequency of rs3128917 T allele (p = 0.054). These alleles were associated with an increased chance of HBV clearance (rs3077: OR = 1.41, p = 0.0083; rs9277378: OR = 1.61, p = 0.00011; rs3128917: OR = 1.54, p = 0.00017). Significant associations between HLA-DP genotypes and HBV clearance were also found under different genetic models. Haplotype TAT was associated with an increased chance of HBV clearance (OR = 1.64, p = 0.0013). No association was found between these SNPs and HBV disease activity.
Conclusion
HLA-DP SNPs rs3077, rs9277378 and rs3128917 were associated with chronicity of HBV disease in the Chinese. Further studies are required to determine whether these SNPs influence the disease endemicity in different ethnic populations.
doi:10.1371/journal.pone.0066920
PMCID: PMC3692552  PMID: 23825586
19.  Hepatitis B Virus (HBV) Subgenotypes C2 and B2 Differ in Lamivudine- and Adefovir-Resistance-Associated Mutational Patterns in HBV-Infected Chinese Patients▿  
Journal of Clinical Microbiology  2010;48(12):4363-4369.
We aimed to study the prevalence and clinical implications of hepatitis B virus (HBV) subgenotypes in Chinese patients. A total of 4,300 patients, mainly from northern China, were enrolled, including 182 patients with acute hepatitis B and 4,118 patients with chronic HBV infection who had been exposed to nucleoside or nucleotide analogs. HBV genotypes/subgenotypes were determined by direct sequencing of the HBV S/Pol region. The prevalence rates were 0.40% for HBV/B1, 14.30% for HBV/B2, 0.25% for HBV/B3, 0.35% for HBV/B4, 1.05% for HBV/C1, 81.72% for HBV/C2, 0.93% for HBV/C3, 0.16% for HBV/C4, and 0.84% for HBV/D. In chronic HBV infection, patients with HBV/B2 were younger and had lower ΗBeAg positive rates than patients with HBV/C2. The incidence of lamivudine-resistant mutations was significantly higher in HBV/C2 compared to HBV/B2 (27.9% versus 19.8%; P < 0.01), and the significant difference was observed only for rtM204I and not rtM204V. In addition, compensatory mutations were more frequently detected in HBV/C2. The incidence of adefovir-resistant mutations was similar between the two subsets, but HBV/C2 inclined to show rtA181V (3.6% for C2 versus 0.9% for B2; P < 0.01), while HBV/B2 inclined to show rtN236T (4.5% for versus 2.5% for C2; P < 0.01). The ratios of HBV/B2 to HBV/C2 infection were 1.7 (110/65), 5.7 (2,653/463), 7.5 (520/69), 8.0 (48/6), and 15.3 (183/12) for acute hepatitis B, chronic hepatitis B, liver cirrhosis, acute-on-chronic liver failure, and hepatocellular carcinoma, respectively. In conclusion, HBV/C2 and HBV/B2, two prevalent subgenotypes, differ in lamivudine- and adefovir-resistance-associated mutational patterns. HBV/C2-infected patients are more likely to have disease progression than HBV/B2-infected ones.
doi:10.1128/JCM.01518-10
PMCID: PMC3008443  PMID: 20881176
20.  Massive APOBEC3 Editing of Hepatitis B Viral DNA in Cirrhosis 
PLoS Pathogens  2010;6(5):e1000928.
DNA viruses, retroviruses and hepadnaviruses, such as hepatitis B virus (HBV), are vulnerable to genetic editing of single stranded DNA by host cell APOBEC3 (A3) cytidine deaminases. At least three A3 genes are up regulated by interferon-α in human hepatocytes while ectopic expression of activation induced deaminase (AICDA), an A3 paralog, has been noted in a variety of chronic inflammatory syndromes including hepatitis C virus infection. Yet virtually all studies of HBV editing have confined themselves to analyses of virions from culture supernatants or serum where the frequency of edited genomes is generally low (≤10−2). We decided to look at the nature and frequency of HBV editing in cirrhotic samples taken during removal of a primary hepatocellular carcinoma. Forty-one cirrhotic tissue samples (10 alcoholic, 10 HBV+, 11 HBV+HCV+ and 10 HCV+) as well as 4 normal livers were studied. Compared to normal liver, 5/7 APOBEC3 genes were significantly up regulated in the order: HCV±HBV>HBV>alcoholic cirrhosis. A3C and A3D were up regulated for all groups while the interferon inducible A3G was over expressed in virus associated cirrhosis, as was AICDA in ∼50% of these HBV/HCV samples. While AICDA can indeed edit HBV DNA ex vivo, A3G is the dominant deaminase in vivo with up to 35% of HBV genomes being edited. Despite these highly deleterious mutant spectra, a small fraction of genomes survive and contribute to loss of HBeAg antigenemia and possibly HBsAg immune escape. In conclusion, the cytokine storm associated with chronic inflammatory responses to HBV and HCV clearly up regulates a number of A3 genes with A3G clearly being a major restriction factor for HBV. Although the mutant spectrum resulting from A3 editing is highly deleterious, a very small part, notably the lightly edited genomes, might help the virus evolve and even escape immune responses.
Author Summary
Retroviruses and hepadnaviruses such as hepatitis B virus (HBV) are vulnerable to mutation by host cell single stranded DNA cytidine deaminases. The result is hypermutated viral peppered with uracil residues. While there are potentially 11 such human enzymes, the major players belong to the 7 gene APOBEC3 cluster on chromosome 22, some of which can be activated by anti-viral interferons. We investigated the nature and frequency of HBV editing in 41 cirrhotic samples following surgical removal of primary hepatocellular carcinoma. Numerous APOBEC3 genes were activated in the decreasing order HCV±HBV>HBV>alcoholic cirrhosis. We observed that APOBEC3G was the dominant restricting factor in vivo with up to 35% of HBV edited genomes. Among the HBV mutants generated by APOBEC3 editing, we found a small fraction of lightly APOBEC3G edited genomes that can impact HBV replication in vivo and possibly immune escape.
doi:10.1371/journal.ppat.1000928
PMCID: PMC2877740  PMID: 20523896
21.  Early Detection, Curative Treatment, and Survival Rates for Hepatocellular Carcinoma Surveillance in Patients with Cirrhosis: A Meta-analysis 
PLoS Medicine  2014;11(4):e1001624.
Amit Singal and colleagues conducted a systematic review of the evidence that surveillance for hepatocellular carcinoma in patients with cirrhosis improves early detection, receipt of curative treatment, and overall survival.
Please see later in the article for the Editors' Summary
Background
Surveillance for hepatocellular carcinoma (HCC) has level I evidence among patients with hepatitis B but only level II evidence in patients with cirrhosis. This lack of randomized data has spurred questions regarding the utility of HCC surveillance in this patient population; however, lack of randomized data does not equate to a lack of data supporting the efficacy of surveillance. The aim of our study was to determine the effect of HCC surveillance on early stage tumor detection, receipt of curative therapy, and overall survival in patients with cirrhosis.
Methods and Findings
We performed a systematic literature review using Medline from January 1990 through January 2014 and a search of national meeting abstracts from 2009–2012. Two investigators identified studies that reported rates of early stage tumor detection, curative treatment receipt, or survival, stratified by HCC surveillance status, among patients with cirrhosis. Both investigators independently extracted data on patient populations, study methods, and results using standardized forms. Pooled odds ratios, according to HCC surveillance status, were calculated for each outcome using the DerSimonian and Laird method for a random effects model.
We identified 47 studies with 15,158 patients, of whom 6,284 (41.4%) had HCC detected by surveillance. HCC surveillance was associated with improved early stage detection (odds ratio [OR] 2.08, 95% CI 1.80–2.37) and curative treatment rates (OR 2.24, 95% CI 1.99–2.52). HCC surveillance was associated with significantly prolonged survival (OR 1.90, 95% CI 1.67–2.17), which remained significant in the subset of studies adjusting for lead-time bias. Limitations of current data included many studies having insufficient duration of follow-up to assess survival and the majority not adjusting for liver function or lead-time bias.
Conclusions
HCC surveillance is associated with significant improvements in early tumor detection, receipt of curative therapy, and overall survival in patients with cirrhosis.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Hepatocellular cancer (HCC) is the commonest form of primary liver cancer—a type of cancer that starts when a cell in the liver acquires genetic changes that allow it to grow uncontrollably. Primary liver cancer is the third leading cause of cancer-related death worldwide, killing more than 600,000 people every year. The symptoms of HCC are vague and rarely appear until the cancer has spread throughout the liver. They include unexplained weight loss, feeling sick, tiredness, and jaundice (yellowing of the skin and eyes). If liver cancer is diagnosed in its early stages, it can be treated by surgically removing part of the liver, by liver transplantation, or by a procedure called radiofrequency ablation in which an electric current is used to destroy the cancer cells. However, most people are diagnosed with HCC when the cancer is advanced and cannot be treated. These individuals are given palliative treatment to relieve pain and discomfort. Although most patients who are diagnosed with HCC at an early stage survive more than 5 years, patients with more advanced HCC have an average survival less than one year. The exact cause of HCC is unknown, but it is thought to be related to cirrhosis (scarring) of the liver. This condition is the end result of long-term (chronic) liver damage caused by, for example, alcohol abuse or infection with hepatitis B virus (HBV).
Why Was This Study Done?
Because HCC tends to be untreatable when it is diagnosed at a late stage, if the tumor can be found early by regularly measuring blood levels of alpha fetoprotein (a liver cancer biomarker) and using ultrasound, outcomes for patients at high risk of developing HCC might be improved. Indeed, American and European guidelines recommend HCC surveillance with ultrasound every 6 months in patients with HBV infection and/or cirrhosis. However, although randomized controlled trial results support HCC surveillance among patients infected with HBV, no randomized trials have investigated its use among patients with cirrhosis. Here, the researchers use predefined criteria to identify all the published cohort and case-control studies (two types of non-randomized studies) that have examined the impact of HCC surveillance on outcomes in patients with cirrhosis. They then pool the data from these studies using a statistical approach called meta-analysis to estimate whether HCC surveillance is associated with improvements in early tumor detection, curative treatment receipt, and survival rates among patients with cirrhosis.
What Did the Researchers Do and Find?
The researchers identified 47 studies that examined the association of HCC surveillance with outcomes in 15,158 patients with cirrhosis who developed HCC. In 41.4% of these patients, HCC was detected by surveillance. Among patients who had undergone HCC surveillance, the pooled rate of early detection was 70.9%, whereas among patients who had not undergone surveillance but who were diagnosed incidentally or who presented with symptoms, the pooled rate of early detection was 29.9%. The researchers calculated that the pooled odds (chances) of early detection among patients undergoing surveillance compared to early detection among patients not undergoing surveillance was 2.08 (an odds ratio [OR] of 2.08). The pooled rate of curative treatment receipt among patients undergoing surveillance was 51.3% compared to only 23.8% among patients not undergoing surveillance (OR 2.24). Finally, among those patients for whom the relevant data were available, 50.8% of patients who had undergone HCC surveillance but only 28.2% of those who had not undergone surveillance survived for at least 3 years after diagnosis (OR 1.90).
What Do These Findings Mean?
These findings show that HCC surveillance is associated with significant improvements (improvements that are unlikely to have happened by chance) in early tumor detection, receipt of curative treatment, and overall survival among patients with cirrhosis. Importantly, the association with improved overall survival remained significant after adjusting for the possibility that patients who underwent surveillance died at the same time as they would have done without surveillance but appeared to survive longer because they were diagnosed earlier (this is called adjustment for lead-time bias). These results must be interpreted cautiously, however, because many of the studies included in the meta-analysis had insufficient follow-up to assess survival adequately, not all the studies adjusted for lead-time bias, and none of the studies assessed potential downstream harms of HCC surveillance such as complications of liver biopsies. Nevertheless, overall, these findings provide sufficient evidence to support guidelines that recommend regular HCC surveillance for patients with cirrhosis.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001624.
The US National Cancer Institute provides information about all aspects of cancer, including detailed information for patients and professionals about primary liver cancer and about screening for primary liver cancer (in English and Spanish)
The American Cancer Society also provides information about liver cancer (available in several languages)
The UK National Health Service Choices website provides information about primary liver cancer and about cirrhosis (including patient stories)
Cancer Research UK (a not-for-profit organization) also provides detailed information about primary liver cancer
MedlinePlus provides links to further resources about liver cancer and cirrhosis (in English and Spanish)
Information is available at the American Liver Foundation
American Association for the Study of Liver Diseases provides practice guidelines
doi:10.1371/journal.pmed.1001624
PMCID: PMC3972088  PMID: 24691105
22.  Relationship between interleukin-6 polymorphism and susceptibility to chronic hepatitis B virus infection 
AIM: To identify the relationship between tag single nucleotide polymorphisms (tag SNPs) of interleukin-6 (IL-6) gene and susceptibility to chronic hepatitis B virus (HBV) infection in a Han Chinese population.
METHODS: We performed a case-control study of 501 Chinese patients with chronic HBV infection and 301 self-limiting HBV-infected individuals as controls. Genomic DNA was isolated from the whole blood of all subjects using phenol/chloroform with MaXtract high-density tubes. Tag SNPs were identified using genotype data from the panel (Han Chinese in Beijing) of the phase II HapMap Project. Four tag SNPs in IL-6 (rs17147230A/T, rs2066992G/T, rs2069837A/G and rs2069852A/G) were genotyped by the Multiplex Snapshot technique. The genotype and allele frequencies were calculated and analyzed.
RESULTS: Five haplotypes were involved in the analysis, with frequencies higher than 0.03. One of the haplotypes, TTAA, was significantly different between the two groups. Overall haplotype P values were: ATAA, P = 0.605, OR (95%CI) = 1.056 (0.860-1.297); TGAG, P = 0.385, OR (95%CI) = 1.179 (0.813-1.709); TGGG, P = 0.549, OR (95%CI) = 1.087 (0.827-1.429); TTAA, P = 0.004, OR (95%CI) = 0.655 (0.491-0.873); TTAG, P = 0.266, OR (95%CI) = 1.272 (0.832-1.944). However, the four SNPs showed no significant genotype/allele associations with susceptibility to chronic HBV infection. Overall allele P values were: rs17147230, P = 0.696, OR (95%CI) = 1.041 (0.850-1.276); rs2066992, P = 0.460, OR (95%CI) = 1.090 (0.868-1.369); rs2069837, P = 0.898, OR (95%CI) = 0.983 (0.759-1.274); rs2069852, P = 0.165, OR (95%CI) = 0.859 (0.693-1.064). Overall genotype P values were: rs17147230, P = 0.625; rs2066992, P = 0.500; rs2069837, P = 0.853; and rs2069852, P = 0.380.
CONCLUSION: The four tag SNPs of IL-6 gene may be associated with susceptibility to chronic HBV infection in the Han Chinese population.
doi:10.3748/wjg.v19.i40.6888
PMCID: PMC3812490  PMID: 24187466
Chronic hepatitis B virus infection; Interleukin-6; Single nucleotide polymorphism; Genetic susceptibility; Haplotype
23.  Hepatitis B Virus Core Promoter Mutations in Patients With Chronic Hepatitis B and Hepatocellular Carcinoma in Bucharest, Romania 
Hepatitis Monthly  2014;14(10):e22072.
Background:
Accurate and personalized molecular virological diagnosis of hepatitis B virus (HBV) infection is crucial for individualized selection of patients for antiviral therapy in Romania.
Objectives:
We aimed to investigate HBV mutations in Romanian patients with chronic HBV infection, also to match HBV genotypes with HBV mutations identified and clinical outcomes.
Patients and Methods:
This was a cross-sectional study. A total of 484 Romanian patients with chronic HBV infection and hepatocellular carcinoma (HCC) were investigated. This was performed in Fundeni Clinical Institute, Bucharest, Romania during January 2005 to August 2010. HBsAg positive patients with chronic HBV infection admitted to Fundeni Clinical Institute were randomly enrolled in the study. Analysis was performed in the Centre for Immunogenetics and Virology, Fundeni Clinical Institute, Bucharest, Romania. Indirect diagnosis was performed with enhanced chemiluminescence method using Architect i2000SR and HBV-DNA was quantified with COBAS TaqMan HBV PCR. Direct sequencing of the PCR-products was performed with the PCR-product sequencing kit. HBV genotyping was performed with INNO-LiPA DR Amplification and INNO-LiPA HBV precore-core.
Results:
We detected two HBV genotypes; A (8.1%) and D (60.5%), and a mixture of genotypes A and D (31.4%) (P < 0.001). Basal core promoter (BCP) A1762T/G1764A and precore (PC) G1896A mutations were detected in these Romanian patients with chronic HBV infection. HBV chronic carriers had mainly genotype D (54.4%) and HBV WT (64.0%). BCP A1762T, G1764A and PC G1896A were significantly associated with HCC-tissue HBV sequencing (75.3%) (P < 0.001). PC G1896A alone was detected in HCC-serum HBV sequencing group (66.7%).
Conclusions:
Genotype D was the main genotype detected in Romanian patients with chronic HBV infection. Genotype D presented both BCP and PC mutations more frequently.
doi:10.5812/hepatmon.22072
PMCID: PMC4250966  PMID: 25477976
Hepatitis B Virus; Hepatocellular carcinoma; Genotype; Mutations
24.  Predominance of precore mutations and clinical significance of basal core promoter mutations in chronic hepatitis B virus infection in Indonesia 
Biomedical Reports  2013;1(4):522-528.
Chronic hepatitis B virus (HBV) infection is a major health problem worldwide, with a particularly high prevalence in the Asian-Pacific region. During chronic hepatitis B virus (HBV) infection, mutations commonly occur in the basal core promoter (BCP) and precore (PC) regions of HBV, affecting HBeAg expression, particularly following HBeAg serocon-version. Mutations in the B- and T-cell epitopes of the HBV core have also been observed during disease progression. The clinical significance of HBV genome variability has been demonstrated, however the results are a subject of controversy. Considering the characteristics of the virus associated with geographical location, the profiles of BCP, PC and core mutations and their clinical implications in patients with chronic HBV infection in Surabaya, Indonesia, were investigated. The BCP, PC and core mutations and HBV genotypes were detected by direct sequencing. The HBeAg/anti-HBe status and HBV DNA levels were also assessed. This study enrolled 10 patients with chronic HBV infection (UC) from Dr Soetomo General Hospital and Indonesian Red Cross, Surabaya, East Java, Indonesia, 10 patients with chronic hepatitis B and liver cirrhosis (LC) and 4 patients with chronic hepatitis B and hepatocellular carcinoma (HCC) from Dr Soetomo General Hospital. The PC mutation A1896 was predominant in all the groups (60–100%), together with the PC variant T1858, which was associated with HBV genotype B. The number of detected core mutations (Thr/Ser130) was higher in HCC patients (50%). However, the BCP mutations T1762/A1764 were predominant in LC patients (50–60%). The LC and HCC patients carried HBV isolates with additional mutations, at least at BCP or PC, mainly following HBeAg seroconversion. In the majority of anti-HBe-positive samples, the BCP T1762/A1764 mutations were associated with a high viral load, regardless of the PC 1896 status. In conclusion, the PC mutations were found to be predominant in all the groups. However, the BCP mutations were mainly detected in the LC group and may be considered as a critical indicator of a poor clinical outcome.
doi:10.3892/br.2013.106
PMCID: PMC3917060  PMID: 24648979
hepatitis B virus; precore mutations; basal core promoter mutations; core mutations; chronic hepatitis B virus infection
25.  RANTES, MCP-1, CCR2, CCR5, CXCR1 and CXCR4 Gene Polymorphisms are not Associated with the Outcome of Hepatitis B Virus Infection: Results from a Large Scale Single Ethnic Population 
Journal of Korean Medical Science  2007;22(3):529-535.
Recovery from hepatitis B virus (HBV) infection depends on the cellular immune responses. Chemokines and their receptors play significant roles in immune defense. This study was undertaken to investigate the association between HBV infection and single nucleotide polymorphisms (SNPs) of genes for the chemokines and their receptors. Between March 2002 and February 2004, a total of 957 single ethnic Korean patients were enrolled into two different groups; "HBV clearance group" (n=350), who have recovered from HBV infection, and "HBV persistence group" (n=607), who were repeatedly HBsAg-positive. The HBV persistence group was subdivided into "inactive carrier" and "HBV progression group (chronic hepatitis and cirrhosis)". We assessed polymorphisms in regulated and normal T-cell expressed and secreted (RANTES) at position -403, monocyte chemoattractant protein-1 (MCP-1) at position -2518, CCR2 V64I, CCR5 -2459, CXCR1 S276T and CXCR4 I138I using single primer extension assay. Genotype distributions of the "HBV clearance versus persistence group" and "inactive carrier versus HBV progression group" were compared. On the basis of unconditional logistic regression analysis with adjustment for age and sex, no statistically significant association with susceptibility to persistent HBV infection was observed with RANTES -403, MCP-1 -2518, CCR2 V64I, CCR5 -2459, CXCR1 S276T, and CXCR4 I138I polymorphisms. In addition, no association of analyzed SNPs with HBV disease progression was found.
doi:10.3346/jkms.2007.22.3.529
PMCID: PMC2693650  PMID: 17596666
Hepatitis B; Single Nucleotide Polymorphism (SNP); Chemokines; Chemokine Receptors

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