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      Identification of novel susceptibility loci associated with hepatitis B surface antigen seroclearance in chronic hepatitis B

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          Abstract

          Background/Aims

          The seroclearance of hepatitis B virus (HBV) surface antigen (HBsAg) is regarded as a functional cure of chronic hepatitis B (CHB) although it occurs rarely. Recently, several genome-wide association studies (GWASs) revealed various genetic alterations related to the clinical course of HBV infection. However, all of these studies focused on the progression of HBV infection to chronicity and had limited application because of the heterogeneity of HBV genotypes. In the present study, we aimed to determine susceptibility genetic markers for seroclearance of HBsAg in CHB patients with a homogenous viral genotype.

          Methods

          One hundred patients with CHB who had experienced HBsAg seroclearance before 60 years of age and another 100 with CHB showing high serum levels of HBsAg even after 60 years of age were enrolled. Extreme-phenotype GWAS was conducted using blood samples of participants.

          Results

          We identified three single nucleotide polymorphisms, rs7944135 ( P = 4.17 × 10 −6, odds ratio [OR] = 4.16, 95% confidence interval [CI] = 2.27–7.63) at 11q12.1, rs171941 ( P = 3.52×10 −6, OR = 3.69, 95% CI = 2.13–6.42) at 5q14.1, and rs6462008 ( P = 3.40×10 −6, OR = 0.34, 95% CI = 0.22–0.54) at 7p15.2 as novel susceptibility loci associated with HBsAg seroclearance in patients with CHB. The flanking genes at these loci including MPEG1, DTX4, MTX3, and HOXA13 were suggested to have functional significance. In addition, through functional analysis, CXCL13 was also presumed to be related.

          Conclusions

          To the best of our knowledge, this study is the first GWAS regarding the seroclearance of HBsAg in CHB patients. We identify new susceptibility loci for cure of CHB, providing new insights into its pathophysiology.

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          Most cited references 44

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          A global reference for human genetic variation

           Lachlan Coin (2017)
          The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.
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            Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity.

            Chronic hepatitis B virus infection is one of the most serious infections and a major risk factor for deaths from cirrhosis and liver cancer. We estimate age-, sex- and region-specific prevalence of chronic HBV infection and calculate the absolute number of persons being chronically infected. A systematic review of the literature for studies reporting HBV infection was conducted and worldwide HBsAg seroprevalence data was collected over a 27-year period (1980-2007). Based on observed data, age-specific prevalence and endemicity were estimated on a global level and for all world regions for 1990 and 2005 using an empirical Bayesian hierarchical model. From 1990 to 2005, the prevalence of chronic HBV infection decreased in most regions. This was particularly evident in Central sub-Saharan Africa, Tropical and Central Latin America, South East Asia and Central Europe. Despite this decrease in prevalence, the absolute number of HBsAg positive persons increased from 223 million in 1990 to 240 million in 2005. Age-specific prevalence varied by geographical region with highest endemicity levels in sub-Saharan Africa and prevalence below 2% in regions such as Tropical and Central Latin America, North America and Western Europe. Asian regions showed distinct prevalence patterns with lower intermediate prevalence in South Asia, but up to 8.6% HBsAg prevalence in East Asia. Strong declines were seen in South East Asian children. Declines in HBV infection prevalence may be related to expanded immunization. The increasing overall number of individuals being chronically infected with HBV, and the widespread global differences in HBV prevalence call for targeted approaches to tackle HBV-related mortality and morbidity. HBV infection prevalence data are needed at country and sub-national level to estimate disease burden and guide health and vaccine policy. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.

              Hepatitis B virus (HBV) infection remains a global public health problem with changing epidemiology due to several factors including vaccination policies and migration. This Clinical Practice Guideline presents updated recommendations for the optimal management of HBV infection. Chronic HBV infection can be classified into five phases: (I) HBeAg-positive chronic infection, (II) HBeAg-positive chronic hepatitis, (III) HBeAg-negative chronic infection, (IV) HBeAg-negative chronic hepatitis and (V) HBsAg-negative phase. All patients with chronic HBV infection are at increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC), depending on host and viral factors. The main goal of therapy is to improve survival and quality of life by preventing disease progression, and consequently HCC development. The induction of long-term suppression of HBV replication represents the main endpoint of current treatment strategies, while HBsAg loss is an optimal endpoint. The typical indication for treatment requires HBV DNA >2,000IU/ml, elevated ALT and/or at least moderate histological lesions, while all cirrhotic patients with detectable HBV DNA should be treated. Additional indications include the prevention of mother to child transmission in pregnant women with high viremia and prevention of HBV reactivation in patients requiring immunosuppression or chemotherapy. The long-term administration of a potent nucleos(t)ide analogue with high barrier to resistance, i.e., entecavir, tenofovir disoproxil or tenofovir alafenamide, represents the treatment of choice. Pegylated interferon-alfa treatment can also be considered in mild to moderate chronic hepatitis B patients. Combination therapies are not generally recommended. All treated and untreated patients should be monitored for treatment response and adherence, and the risk of progression and development of complications. HCC remains the major concern for treated chronic hepatitis B patients. Several subgroups of patients with HBV infection require specific focus. Future treatment strategies to achieve 'cure' of disease and new biomarkers are discussed.
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                Author and article information

                Contributors
                Role: Formal analysisRole: InvestigationRole: Writing – original draft
                Role: Formal analysisRole: InvestigationRole: Writing – original draft
                Role: Formal analysisRole: Visualization
                Role: Data curationRole: Investigation
                Role: Formal analysis
                Role: Formal analysis
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Funding acquisitionRole: Methodology
                Role: ConceptualizationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                5 July 2018
                2018
                : 13
                : 7
                Affiliations
                [1 ] Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
                [2 ] Department of Physiology, Ajou University School of Medicine, Suwon, Korea
                [3 ] Department of Biomedical Science, Graduate School, Ajou University, Suwon, Korea
                [4 ] Department of Computer Science and Engineering, Korea University College of Informatics, Seoul, Korea
                Universita degli Studi di Pisa, ITALY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                PONE-D-17-38758
                10.1371/journal.pone.0199094
                6033413
                29975729
                © 2018 Kim et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Counts
                Figures: 4, Tables: 3, Pages: 15
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100003725, National Research Foundation of Korea;
                Award ID: NRF-2012R1A5A2048183
                Award Recipient :
                This work was funded in full by the National Research Foundation of Korea (NRF; https://www.nrf.re.kr) funded by the Korea government (MSIP), grant number NRF-2012R1A5A2048183. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Computational Biology
                Genome Analysis
                Genome-Wide Association Studies
                Biology and Life Sciences
                Genetics
                Genomics
                Genome Analysis
                Genome-Wide Association Studies
                Biology and Life Sciences
                Genetics
                Human Genetics
                Genome-Wide Association Studies
                Medicine and health sciences
                Infectious diseases
                Viral diseases
                Hepatitis
                Hepatitis B
                Medicine and health sciences
                Gastroenterology and hepatology
                Liver diseases
                Infectious hepatitis
                Hepatitis B
                Biology and Life Sciences
                Genetics
                Molecular Genetics
                Biology and Life Sciences
                Molecular Biology
                Molecular Genetics
                Biology and Life Sciences
                Biochemistry
                Proteins
                Interferons
                Biology and Life Sciences
                Genetics
                Genetic Loci
                Biology and life sciences
                Microbiology
                Medical microbiology
                Microbial pathogens
                Viral pathogens
                Hepatitis viruses
                Hepatitis B virus
                Medicine and health sciences
                Pathology and laboratory medicine
                Pathogens
                Microbial pathogens
                Viral pathogens
                Hepatitis viruses
                Hepatitis B virus
                Biology and life sciences
                Organisms
                Viruses
                Viral pathogens
                Hepatitis viruses
                Hepatitis B virus
                Biology and Life Sciences
                Genetics
                Human Genetics
                Biology and Life Sciences
                Genetics
                Heredity
                Genetic Mapping
                Haplotypes
                Custom metadata
                All relevant data are available from figshare: https://figshare.com/articles/gtReport_txt/6614975 (DOI: 10.6084/m9.figshare.6614975).

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