|
1
|
Zhao Y, Chen K, Yang H, Zhang F, Ding L, Liu Y, Zhang L, Zhang Y, Wang H, Deng Y. HLA-DR genetic polymorphisms and hepatitis B virus mutations affect the risk of hepatocellular carcinoma in Han Chinese population. Virol J 2023; 20:283. [PMID: 38037048 PMCID: PMC10691135 DOI: 10.1186/s12985-023-02253-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 11/26/2023] [Indexed: 12/02/2023] Open
Abstract
BACKGROUND Human leucocyte antigen (HLA)-DR plays a crucial role in the immune response against hepatitis B virus (HBV). We aimed to investigate the associations of HLA-DR single nucleotide polymorphisms (SNPs) with the generation of hepatocellular carcinoma (HCC)-related HBV mutations. The effects of HLA-DR SNPs and their interactions with HBV mutations on HCC risks were also determined. METHODS Five HLA-DR SNPs (rs3135363, rs9268644, rs35445101, rs24755213, and rs984778) were genotyped in 792 healthy controls, 586 chronic hepatitis B (CHB) patients, 536 liver cirrhosis (LC) patients, and 1500 HCC patients using quantitative PCR. Sanger sequencing was used to identify the HBV mutations. Logistic regression model was performed to evaluate the association of HLA-DR SNPs with HCC risk and the frequencies of HCC-related HBV mutations. RESULTS The variant genotypes at rs3135363, rs9268644, rs35445101, rs24755213, and rs984778 were associated with decreased HCC risks. In genotype C HBV-infected subjects, variant genotypes of these SNPs were associated with decreased frequencies of HCC-related HBV mutations such as C1653T, T1674C/G, G1719T, T1753A/C, A1762T/G1764A, A1846T, G1896A, G1899A, and preS deletion. AG genotype at rs3135363, CA genotype at rs9268644, and AG genotype at rs24755213 reduced the generation of T1753A/C and G1896A in genotype B HBV-infected subjects, respectively. In addition, the interactions of rs3135363, rs9268644, rs24755213 with C1653T, T1753A/C, A1846T, and G1896A decreased the risks of HCC. CONCLUSIONS HLA-DR genetic polymorphisms might predispose the host to immunoselection of HCC-related HBV mutations and affect the HCC risks possibly through interacting with HBV mutations.
Collapse
Affiliation(s)
- Yubao Zhao
- Department of Infectious Diseases, Second Affiliated Hospital of Shandong First Medical University, 706 Taishan Street, Tai'an, Shandong Province, China
| | - Kun Chen
- School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, 6699 Qingdao Road, Jinan, Shandong Province, China
| | - Hui Yang
- School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, 6699 Qingdao Road, Jinan, Shandong Province, China
| | - Feng Zhang
- Department of Gastrointestinal Surgery, Tai'an Central Hospital, 29 Longtan Road, Tai'an, Shandong Province, China
| | - Lu Ding
- Department of Public Health, Jinan Central Hospital, 105 Jiefang Road, Jinan, Shandong Province, China
| | - Yan Liu
- School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, 6699 Qingdao Road, Jinan, Shandong Province, China
| | - Le Zhang
- School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, 6699 Qingdao Road, Jinan, Shandong Province, China
| | - Yuchen Zhang
- School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, 6699 Qingdao Road, Jinan, Shandong Province, China
| | - Huiliang Wang
- Department of Infectious Diseases, Second Affiliated Hospital of Shandong First Medical University, 706 Taishan Street, Tai'an, Shandong Province, China
| | - Yang Deng
- School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, 6699 Qingdao Road, Jinan, Shandong Province, China.
| |
Collapse
|
|
2
|
Akgöllü E, Demirkazık M, Bilgin R. The effect of HLA-DP gene polymorphisms in Plasmodium Vivax-induced malaria susceptibility. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2023; 43:572-584. [PMID: 37980631 DOI: 10.1080/15257770.2023.2283620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 11/08/2023] [Indexed: 11/21/2023]
Abstract
Plasmodium vivax is the second most common Plasmodium parasite causing clinically serious symptoms and death from malaria. It is an important cause of morbidity and mortality, especially in Asia, the Middle East, and South America. Human leukocyte antigen molecules are responsible for presenting foreign antigens to T cells. Polymorphisms in HLA genes affect antigen presentation. HLA alleles involved in the presentation of P. vivax antigens affect the antibody response. The present study aimed to reveal the relationship of rs3077 and rs9277535 polymorphisms in HLA-DP genes with malaria caused by P. vivax for the first time in the worldwide. In the present research, rs3077 and rs9277535 polymorphisms were investigated in a case-control study of 124 patients with P. vivax-induced malaria and 211 healthy persons by using a real-time polymerase chain reaction (RT-PCR). The results showed that the G alleles of rs3077 and rs9277535 polymorphisms were detected as protective alleles, while the A alleles of both polymorphisms increase the risk of susceptibility to malaria disease. The results of the present study showed that both polymorphisms have a major effect on the susceptibility to malaria caused by P. vivax. We recommend that this study should be conducted in a different population with a larger sample size to confirm our results.
Collapse
Affiliation(s)
- Ersin Akgöllü
- Patnos Vocational School, Department of Pharmacy, Ağrı İbrahim Çeçen University, Merkez/Ağrı, Turkey
| | - Mehtap Demirkazık
- Faculty of Medicine, Department of Parasitology, Çukurova University, Adana, Turkey
| | - Ramazan Bilgin
- Faculty of Science, Department of Chemistry, Çukurova University, Adana, Turkey
| |
Collapse
|
|
3
|
Naderi M, Hosseini SM, Behnampour N, Shahramian I, Moradi A. Association of HLADQ-B1 polymorphisms in three generations of chronic hepatitis B patients. Virus Res 2023; 325:199036. [PMID: 36592642 DOI: 10.1016/j.virusres.2022.199036] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 12/28/2022] [Accepted: 12/29/2022] [Indexed: 12/31/2022]
Abstract
The presence of polymorphisms in the human leukocyte antigen (HLA)-DQB1 gene, along with its expression, has been demonstrated to be correlated with spontaneous clearance and susceptibility to HBV infection. The present study aimed to evaluate the possible role of genetic polymorphisms in HLA-DQB1 in three generations of patients with chronic hepatitis B (CHB). Based on the inclusion criteria, 90 CHB patients, 18 individuals recovered from HBV infection, and 40 healthy subjects were chosen. The DNA contents of the whole blood samples were extracted in order to perform HLA-DQB1 typing by the PCR technique. Besides whole blood samples, sera were applied to measure liver function tests (LFTs), as well as the titers of anti-HDV and anti-HCV. Also, in all CHB patients were measured liver stiffness (LSM) by Fibro Scan. The results of HLA-DQB1 polymorphisms (rs2856718 and rs7453920) demonstrated that the majority of polymorphisms in CHB patients were HLA-DQB1*03, HLA-DQB1*05, HLA-DQB1*04:01 and HLA-DQB1*03:01 that associated with HBV persistence and chronicity. Among the patients who showed these polymorphisms, the mean±SD, LSM was 4±1.57 KPa and most of them, F grade was reported as F2, which was a sign of disease progression towards chronicity. HLA polymorphisms imputation revealed that HLA-DQB1*06:04 (3.4%, P-Value= 0.2) was detected only in healthy subjects as protective polymorphism, while the allele HLA-DQB1*03:03 was reported in both healthy subjects (P-Value= 0.06) and recovered patients (P-Value= 0.1) as suppressor of CHB formation. The allele HLA-DQB1*05:02 was found in both healthy subjects (3.4%) and CHB patients (4.5%) which was associated with risk to liver cirrhosis (P-Value= 0, OR: 0.002 0.95CI: 0.000-0.15). HLA polymorphism analysis indicated that 17.39% of patients who were seropositive for anti-HCV carried the HLA-DQB1*03:01. HBV resistance or infection risk could be assessed by DBQ1 typing. The existence of polymorphisms in HLA gene could influence the clearance (HLA-DQB1*03:03) or susceptibility and persistence of infection (HLA-DQB1*03, HLA-DQB1*05, HLA-DQB1*04:01 and HLA-DQB1*03:01). These results have the potential to improve personalized therapy and prognosis for HBV infection.
Collapse
Affiliation(s)
- Malihe Naderi
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran; Department of Microbiology, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Seyed Masoud Hosseini
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran.
| | - Naser Behnampour
- Biostatistics and Epidemiology Department, Faculty of Health, Health Management and Social Development Research Center, Golestan University of Medical Sciences, Golestan, Iran
| | - Iraj Shahramian
- Department of Pediatrics, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abdolvahab Moradi
- Department of Microbiology, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran.
| |
Collapse
|
|
4
|
Sowpati DT, Tallapaka KB. Host genetics in disease susceptibility and protection. GENOMIC SURVEILLANCE AND PANDEMIC PREPAREDNESS 2023:27-48. [DOI: 10.1016/b978-0-443-18769-8.00002-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
|
|
5
|
Mohammadi H, Alavian SM, Sharafi H. Association of single nucleotide polymorphisms in immune-related genes with spontaneous HBsAg seroconversion: A systematic review and meta-analysis. Int Immunopharmacol 2022; 110:108982. [PMID: 35752129 DOI: 10.1016/j.intimp.2022.108982] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 05/28/2022] [Accepted: 06/15/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND Studies have reported that the immune system modulation genes are involved in the seroconversion during hepatitis B virus (HBV) infection. Here, a systematic review with meta-analysis is implemented on the association of polymorphisms in immune-related genes with the spontaneous hepatitis B surface antigen (HBsAg) seroconversion. METHODS A systematic literature search was conducted in the main electronic databases of Scopus, PubMed, and Web of Science before May 2022. Pooled odds ratio (OR) and their corresponding 95% confidence interval (CI) were used to evaluate the strength of the association between genetic polymorphisms and the chance of spontaneous HBsAg seroconversion. RESULTS A total of 40 studies finally included for meta-analysis of 2 HLA-DP SNPs, 2 HLA-DQ SNPs, 3 IFNL3/4 SNPs, 2 IL10 SNPs, and 5 TNF SNPs. Based on the overall pooled analysis, HLA-DP rs3077 A (OR = 1.47, 95%CI: 1.32-1.65), HLA-DP rs9277535 A (OR = 1.48, 95%CI: 1.32-1.66), HLA-DQ rs2856718 G (OR = 1.37, 95%CI: 1.18-1.59), HLA-DQ rs7453920 A (OR = 1.41, 95%CI: 1.04-1.93), IFNL3/4 rs12980275 G (OR = 1.26, 95%CI: 1.01-1.58), TNFA rs1799964 T (OR = 1.17, 95%CI: 1.02-1.35), and TNFA rs1800630 C (OR = 1.26, 95%CI: 1.03-1.55) increased significantly the chance of spontaneous HBsAg seroconversion. CONCLUSION This meta-analysis showed that the HLA-DP gene rs3077 and rs9277535 SNPs, HLA-DQ gene rs2856718 and rs7453920 SNPs, IFNL3/4 gene rs12980275 SNP, TNFA gene rs1799964 and rs1800630 SNPs are involved in the spontaneous HBsAg seroconversion.
Collapse
Affiliation(s)
- Hamed Mohammadi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran; Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Seyed Moayed Alavian
- Middle East Liver Diseases (MELD) Center, Tehran, Iran; Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, Iran
| | | |
Collapse
|
|
6
|
Mizushima D, Hayashida T, Nguyen DHT, Nguyen DT, Matsumoto S, Tanuma J, Gatanaga H, Nguyen KV, Oka S. Possible association of HLA-DP polymorphism and antiretroviral therapy with hepatitis B virus clearance in an HIV-infected Vietnamese population. Glob Health Med 2022; 4:146-151. [PMID: 35855066 PMCID: PMC9243410 DOI: 10.35772/ghm.2021.01113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 03/22/2022] [Accepted: 03/31/2022] [Indexed: 06/15/2023]
Abstract
There is little evidence regarding the association between hepatitis B virus (HBV) chronicity and HLA-DP among the HIV-infected Vietnamese population. To study this, we conducted a cross-sectional analysis and a prospective study involving an HIV-infected Vietnamese cohort. The association between HBV chronicity and HLA-DP single nucleotide polymorphisms (SNPs) of rs3077 and rs9277535 among Vietnamese patients with previous HBV exposure was first evaluated. In addition, treatment-naive patients with chronic HBV infection were followed between 2012 and 2017 for HBV clearance after the initiation of antiretroviral therapy (ART). A total of 820 subjects with previous HBV exposure were included in the cross-sectional study. Among them, 147 (17.9 %) had chronic HBV infection, and 673 (82.1 %) achieved HBV clearance. The proportions of minor allele homozygotes of rs3077 and rs9277535 were 10.9 % and 15.2 % (p = 0.481) and 4.1 % and 11.7 % (p = 0.003), respectively. Multivariate analysis showed that rs9277535 minor homozygote was a significant protective factor against chronic HBV infection (odds ratio [OR], 0.271; 95 % confidence interval [CI]; 0.114-0.642, p = 0.001). Further, none of the 43 patients in the prospective study, who received ART possessed the rs9277535 minor homozygote. The average follow-up period was 4.8 years, and 10 subjects (23.3 %, 4.9 %/person-years) achieved HBV clearance. Univariate analysis revealed that the SNPs were not significantly associated with HBV clearance. In conclusion, our study confirmed that the rs9277535 minor allele homozygote was significantly associated with HBV clearance among HIV-infected Vietnamese patients.
Collapse
Affiliation(s)
- Daisuke Mizushima
- AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Tsunefusa Hayashida
- AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
| | | | | | - Shoko Matsumoto
- AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Junko Tanuma
- AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Hiroyuki Gatanaga
- AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
- Center for AIDS Research, Kumamoto University, Kumamoto, Japan
| | | | - Shinichi Oka
- AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
- Center for AIDS Research, Kumamoto University, Kumamoto, Japan
| |
Collapse
|
|
7
|
Riazalhosseini B, Mohamed R, Devi Apalasamy Y, Mohamed Z. Association of deleted in liver cancer-1 gene polymorphism with increased risk of chronicity of disease among Malaysian patients with hepatitis B infection. Pharmacogenet Genomics 2021; 31:185-190. [PMID: 34320605 DOI: 10.1097/fpc.0000000000000439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE The aim of this study is to examine the association between genetic variations in deleted in liver cancer 1 (DLC1) gene with progression of the hepatitis B virus (HBV) infection. METHODS A total of 623 subjects were included in this study, of whom, 423 were chronic hepatitis B (CHB) patients without liver cirrhosis or hepatocellular carcinoma (HCC), 103 CHB with either liver cirrhosis ± HCC and 97 individuals who had resolved HBV. Two single-nucleotide polymorphisms rs3739298 and rs532841 of DLC1 gene were genotyped using the Sequenom MassARRAY platform. RESULTS Our results indicated significant differences between the chronic HBV and resolved HBV groups in genotype and allele frequencies of DLC1-rs3739298 [odds ratio (OR) = 2.23; 95% confidence interval (CI): 1.24-3.99; P = 0.007] and (OR = 1.54; 95% CI: 1.07-2.22; P = 0.021), respectively. Moreover, haplotype analysis revealed significant associations between chronicity of HBV with TG and GA haplotypes (P = 0.041 and P = 0.042), respectively. CONCLUSION A significant association exists between the rs3739298 variant and susceptibility to CHB infection.
Collapse
Affiliation(s)
| | | | - Yamunah Devi Apalasamy
- Social Wellbeing Research Centre, Faculty of Economics and Administration, University of Malaya, Kuala Lumpur, Malaysia
| | | |
Collapse
|
|
8
|
Abstract
Hepatitis B virus (HBV) can hide in the liver in the form of covalently closed circular DNA. When the body’s immunity changes, HBV reactivation (HBV-R) can occur. The risk of HBV-R is determined by the complex interaction among virological factors, medication factors and host factors. However, many patients do not know that they are infected with HBV, and doctors often do not invest enough time to systematically evaluate the patient’s HBV-R risk factors before immunosuppressive treatment. Therefore, HBV clinical screening should be vigorously promoted to achieve early detection and early prevention for patients with high risk of HBV-R. The mechanism, clinical features, risk factors, HBV-R under different disease etiologies, prevention and treatment of HBV-R were summarized to improve the in-depth understanding and awareness.
Collapse
Affiliation(s)
- Wei Huang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy & Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lingyao Du
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy & Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy & Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| |
Collapse
|
|
9
|
Copley HC, Gragert L, Leach AR, Kosmoliaptsis V. Influence of HLA Class II Polymorphism on Predicted Cellular Immunity Against SARS-CoV-2 at the Population and Individual Level. Front Immunol 2021; 12:669357. [PMID: 34349756 PMCID: PMC8327207 DOI: 10.3389/fimmu.2021.669357] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 06/28/2021] [Indexed: 01/16/2023] Open
Abstract
Development of adaptive immunity after COVID-19 and after vaccination against SARS-CoV-2 is predicated on recognition of viral peptides, presented on HLA class II molecules, by CD4+ T-cells. We capitalised on extensive high-resolution HLA data on twenty five human race/ethnic populations to investigate the role of HLA polymorphism on SARS-CoV-2 immunogenicity at the population and individual level. Within populations, we identify wide inter-individual variability in predicted peptide presentation from structural, non-structural and accessory SARS-CoV-2 proteins, according to individual HLA genotype. However, we find similar potential for anti-SARS-CoV-2 cellular immunity at the population level suggesting that HLA polymorphism is unlikely to account for observed disparities in clinical outcomes after COVID-19 among different race/ethnic groups. Our findings provide important insight on the potential role of HLA polymorphism on development of protective immunity after SARS-CoV-2 infection and after vaccination and a firm basis for further experimental studies in this field.
Collapse
Affiliation(s)
- Hannah C. Copley
- Department of Surgery, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United Kingdom
- European Bioinformatics Institute (EMBL-EBI), Cambridge, United Kingdom
| | - Loren Gragert
- Department of Pathology, Tulane University School of Medicine, New Orleans, LA, United States
- Bioinformatics Research, National Marrow Donor Program, Minneapolis, MN, United States
| | - Andrew R. Leach
- European Bioinformatics Institute (EMBL-EBI), Cambridge, United Kingdom
| | - Vasilis Kosmoliaptsis
- Department of Surgery, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United Kingdom
- National Institute of Health Research (NIHR) Blood and Transplant Research Unit in Organ Donation and Transplantation, University of Cambridge, Cambridge, United Kingdom
- NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom
| |
Collapse
|
|
10
|
Zeng Z, Liu H, Xu H, Lu H, Yu Y, Xu X, Yu M, Zhang T, Tian X, Xi H, Guan L, Zhang J, O'Brien SJ. Genome-wide association study identifies new loci associated with risk of HBV infection and disease progression. BMC Med Genomics 2021; 14:84. [PMID: 33736632 PMCID: PMC7977299 DOI: 10.1186/s12920-021-00907-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 02/17/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Recent studies have identified susceptibility genes of HBV clearance, chronic hepatitis B, liver cirrhosis, hepatocellular carcinoma, and showed the host genetic factors play an important role in these HBV-related outcomes. METHODS Collected samples from different outcomes of HBV infection and performed genotyping by Affymetrix 500 k SNP Array. GCTA tool, PLINK, and Bonferroni method were applied for analysis of genotyping and disease progression. ANOVA was used to evaluate the significance of the association between biomarkers and genotypes in healthy controls. PoMo, FST, Vcftools and Rehh package were used for building the racial tree and population analysis. FST statistics accesses 0.15 was used as a threshold to detect the signature of selection. RESULTS There are 1031 participants passed quality control from 1104 participants, including 275 HBV clearance, 92 asymptomatic persistence infection (ASPI), 93 chronic hepatitis B (CHB), 188 HBV-related decompensated cirrhosis (DC), 214 HBV-related hepatocellular carcinoma (HCC) and 169 healthy controls (HC). In the case-control study, one novel locus significantly associated with CHB (SNP: rs1264473, Gene: GRHL2, P = 1.57 × 10-6) and HCC (SNP: rs2833856, Gene: EVA1C, P = 1.62 × 10-6; SNP: rs4661093, Gene: ETV3, P = 2.26 × 10-6). In the trend study across progressive stages post HBV infection, one novel locus (SNP: rs1537862, Gene: LACE1, P = 1.85 × 10-6), and three MHC loci (HLA-DRB1, HLA-DPB1, HLA-DPA2) showed significant increased progressive risk from ASPI to CHB. Underlying the evolutionary study of HBV-related genes in public database, the derived allele of two HBV clearance related loci, rs3077 and rs9277542, are under strong selection in European population. CONCLUSIONS In this study, we identified several novel candidate genes associated with individual HBV infectious outcomes, progressive stages, and liver enzymes. Two SNPs that show selective significance (HLA-DPA1, HLA-DPB1) in non-East Asian (European, American, South Asian) versus East Asian, indicating that host genetic factors contribute to the ethnic disparities of susceptibility of HBV infection. Taken together, these findings provided a new insight into the role of host genetic factors in HBV related outcomes and progression.
Collapse
Affiliation(s)
- Zheng Zeng
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China.
| | | | | | - Haiying Lu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China
| | - Yanyan Yu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China
| | - Xiaoyuan Xu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China
| | - Min Yu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China
| | - Tao Zhang
- BGI-Shenzhen, Shenzhen, 518083, China
| | - Xiulan Tian
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China
| | - Hongli Xi
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China
| | | | | | - Stephen J O'Brien
- Laboratory of Genomic Diversity, Center for Computer Technologies, ITMO University, St. Petersburg, Russia, 197101.
- Guy Harvey Oceanographic Center, Halmos College of Natural Sciences and Oceanography, Nova Southeastern University, Ft Lauderdale, FL, 33004, USA.
| |
Collapse
|
|
11
|
Xu J, Zhan Q, Fan Y, Yu Y, Zeng Z. Human genetic susceptibility to hepatitis B virus infection. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2021; 87:104663. [PMID: 33278635 DOI: 10.1016/j.meegid.2020.104663] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 11/26/2020] [Accepted: 11/30/2020] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) infection is still a serious health threat worldwide. The outcomes of HBV infection consist of spontaneous HBV clearance and chronic HBV infection. Multiple factors contribute to the disparity of HBV infection outcomes, including host factors, viral factors and environmental factors. The present review comprehends the current researches mainly focusing on the relationships between genetic determinants, including single nucleotide polymorphisms (SNPs) and haplotypes, and susceptibility of HBV infection, namely chronic (persistent) HBV infection and HBV clearance. A number of determinants in the chromosomes, including mutations in human leukocyte antigens (HLAs), cytokines genes, toll-like receptors (TLRs), and other genes are related to the human susceptibility to HBV infection. Among the above variants, some of those in HLAs have been studied and replicated in multiple-ethnic populations and came to consistent conclusions, while some others are novel and need to be evaluated further.
Collapse
Affiliation(s)
- Jinghang Xu
- Department of Infectious Diseases, Peking University First Hospital, Peking University Health Science Center, Beijing 100034, China
| | - Qiao Zhan
- Department of Infectious Diseases, Peking University First Hospital, Peking University Health Science Center, Beijing 100034, China
| | - Yanan Fan
- Department of Infectious Diseases, Peking University First Hospital, Peking University Health Science Center, Beijing 100034, China
| | - Yanyan Yu
- Department of Infectious Diseases, Peking University First Hospital, Peking University Health Science Center, Beijing 100034, China.
| | - Zheng Zeng
- Department of Infectious Diseases, Peking University First Hospital, Peking University Health Science Center, Beijing 100034, China.
| |
Collapse
|
|
12
|
Deng Y, Li P, Liu W, Pu R, Yang F, Song J, Yin J, Han X, Li C, Zhao J, Wang H, Cao G. The genetic polymorphism down-regulating HLA-DRB1 enhancer activity facilitates HBV persistence, evolution and hepatocarcinogenesis in the Chinese Han population. J Viral Hepat 2020; 27:1150-1161. [PMID: 32568442 DOI: 10.1111/jvh.13353] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 05/08/2020] [Accepted: 05/25/2020] [Indexed: 02/06/2023]
Abstract
Genetic predisposition of human leucocyte antigen (HLA)-DR has been linked to nonresponse to hepatitis B virus (HBV) vaccination. We sought to reveal their effects on chronic infection and evolution of HBV and development of hepatocellular carcinoma (HCC). Genetic polymorphisms at HLA-DR enhancer regions were genotyped in 4588 participants using quantitative PCR. HBV mutations were determined by sequencing. A dual-luciferase assay was applied to detect the enhancer activity. Associations between HLA-DR polymorphisms and postoperative prognosis were investigated in another cohort of 397 HBV-infected HCC patients. Variant alleles (rs3135395-T, rs3135338-C and rs477515-T) were significantly associated with a decreased risk of HBV persistence in Chinese patients. rs3135395-T, rs3135338-C, rs477515-T and rs2395178-G also significantly decreased HCC risk. rs3135395-T, rs477515-T and rs2395178-G were inversely associated with the generation of A1762T/G1764A, T1753V and C1653T, the HCC-risk HBV mutations. Multiplicative interactions of the variant genotypes with the HCC-risk HBV mutations were significantly associated with a decreased risk of HCC. In multivariate Cox analysis, rs477515-T independently predicted a favourable prognosis, with a hazard ratio of 0.48 (P = .002). The activity of the HLA-DRB1 enhancer with rs477515-T was significantly higher than that with rs477515-C. The activity of the HLA-DRB1 enhancer with rs477515-T and that with rs477515-C was significantly up-regulated by interferon-γ and interleukin-4, respectively. Interleukin-6 significantly inhibited the HLA-DRB1 enhancer activity, and this effect was more evident in those carrying rs477515-T. Polymorphisms predisposing to down-regulation of HLA-DR facilitate the Th1-to-Th2 transition and promote HCC development, possibly via selecting the HCC-risk HBV mutations. This can be transformed into specific prophylaxis of HCC.
Collapse
Affiliation(s)
- Yang Deng
- Department of Epidemiology, Naval Medical University, Shanghai, China
| | - Peng Li
- Department of Epidemiology, Naval Medical University, Shanghai, China
| | - Wenbin Liu
- Department of Epidemiology, Naval Medical University, Shanghai, China
| | - Rui Pu
- Department of Epidemiology, Naval Medical University, Shanghai, China
| | - Fan Yang
- Department of Epidemiology, Naval Medical University, Shanghai, China
| | - Jiahui Song
- Department of Epidemiology, Naval Medical University, Shanghai, China
| | - Jianhua Yin
- Department of Epidemiology, Naval Medical University, Shanghai, China
| | - Xue Han
- Division of Chronic Diseases, Center for Disease Control and Prevention of Yangpu District, Shanghai, China
| | - Chengzhong Li
- Department of Infectious Diseases, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Jun Zhao
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Hongyang Wang
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology, Shanghai, China
| | - Guangwen Cao
- Department of Epidemiology, Naval Medical University, Shanghai, China.,Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology, Shanghai, China
| |
Collapse
|
|
13
|
Genotyping of immune-related loci associated with delayed HBeAg seroconversion in immune-active chronic hepatitis B patients. Antiviral Res 2020; 176:104719. [PMID: 32004619 DOI: 10.1016/j.antiviral.2020.104719] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 12/26/2019] [Accepted: 01/23/2020] [Indexed: 02/07/2023]
Abstract
The progression of chronic hepatitis B (CHB) is associated with single-nucleotide polymorphisms (SNPs). In this study, we demonstrated the association between immune-related SNPs and delayed spontaneous HBeAg seroconversion in immune-active CHB patients. In addition, we investigated the impact of delayed spontaneous HBeAg seroconversion-related SNPs on HBeAg seroconversion within 3 years during antiviral treatment. We enrolled 332 CHB patients and genotyped 124 SNPs associated with HBV-infected clinical outcomes, including 32 interleukin-related genes, 62 HLA genes, 9 CD marker genes, 7 NK cell receptor genes, and 14 other genes, using ABI OpenArray as a platform. Comparing the immune-active CHB patients with delayed spontaneous HBeAg seroconversion (persistent HBeAg seropositivity, older than 40 years) to those with early inefficient HBeAg seroconversion (HBeAg seroconversion with high viremia, younger than 40 years), logistic analysis revealed that rs3820998 (TANK), rs2621377 (HLA-DOB), rs3130215 (HLA-DPB2), rs2255336 (KLRK1), and rs11614913 (MIR-196A2) were significantly associated with delayed spontaneous HBeAg seroconversion. Using multivariate analysis, we determined that high serum HBV DNA levels (OR = 1.66, 95% CI = 1.33-2.08), rs3820998 (CA, OR = 3.37, 95% CI = 1.24-9.12), rs2621377 (TC, OR = 4.96, 95% CI = 1.85-13.3), rs2255336 (TT, OR = 0.09, 95% CI = 0.01-0.86), and rs11614913 (TT, OR = 2.53, 95% CI = 1.05-6.11) were five independent risk factors for delayed spontaneous HBeAg seroconversion. After patients received nucleos(t)ide analogue treatment, rs3820998 heterozygous CA variant conversely became the only independent favorable factor for treatment-induced HBeAg seroconversion within 3 years (OR = 0.21, 95% CI = 0.06-0.78). These results indicate that distinct immune-related SNPs play a vital role in regulating HBeAg status in immune-active CHB patients with or without antiviral treatment.
Collapse
|
|
14
|
Akgöllü E. Assessment of HLADP gene rs3128917 and rs9380343 polymorphisms in chronic HBV infection. TURKISH JOURNAL OF GASTROENTEROLOGY 2020; 30:616-623. [PMID: 31290749 DOI: 10.5152/tjg.2019.18480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
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.
Collapse
Affiliation(s)
- Ersin Akgöllü
- Department of Gastroenterology, Çukurova University School of Medicine, Adana, Turkey
| |
Collapse
|
|
15
|
Niehrs A, Garcia-Beltran WF, Norman PJ, Watson GM, Hölzemer A, Chapel A, Richert L, Pommerening-Röser A, Körner C, Ozawa M, Martrus G, Rossjohn J, Lee JH, Berry R, Carrington M, Altfeld M. A subset of HLA-DP molecules serve as ligands for the natural cytotoxicity receptor NKp44. Nat Immunol 2019; 20:1129-1137. [PMID: 31358998 PMCID: PMC8370669 DOI: 10.1038/s41590-019-0448-4] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 06/06/2019] [Indexed: 01/25/2023]
Abstract
Natural killer (NK) cells can recognize virus-infected and stressed cells1 using activating and inhibitory receptors, many of which interact with HLA class I. Although early studies also suggested a functional impact of HLA class II on NK cell activity2,3, the NK cell receptors that specifically recognize HLA class II molecules have never been identified. We investigated whether two major families of NK cell receptors, killer-cell immunoglobulin-like receptors (KIRs) and natural cytotoxicity receptors (NCRs), contained receptors that bound to HLA class II, and identified a direct interaction between the NK cell receptor NKp44 and a subset of HLA-DP molecules, including HLA-DP401, one of the most frequent class II allotypes in white populations4. Using NKp44ζ+ reporter cells and primary human NKp44+ NK cells, we demonstrated that interactions between NKp44 and HLA-DP401 trigger functional NK cell responses. This interaction between a subset of HLA-DP molecules and NKp44 implicates HLA class II as a component of the innate immune response, much like HLA class I. It also provides a potential mechanism for the described associations between HLA-DP subtypes and several disease outcomes, including hepatitis B virus infection5-7, graft-versus-host disease8 and inflammatory bowel disease9,10.
Collapse
Affiliation(s)
- Annika Niehrs
- Research Department Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
- German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Wilfredo F Garcia-Beltran
- Research Department Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
| | - Paul J Norman
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado School of Medicine, Aurora, CO, USA
- Department of Microbiology and Immunology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Gabrielle M Watson
- Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia
| | - Angelique Hölzemer
- Research Department Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
- German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
- First Department of Internal Medicine, University Medical Center Eppendorf, Hamburg, Germany
| | - Anaïs Chapel
- Research Department Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
- Unité HIV Inflammation et Persistance, Institut Pasteur, Paris, France
| | - Laura Richert
- Research Department Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
- Inserm Inria SISTM Bordeaux Population Health Research Center UMR 1219, Univ. Bordeaux, Bordeaux, France
| | | | - Christian Körner
- Research Department Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | | | - Glòria Martrus
- Research Department Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Jamie Rossjohn
- Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia
- Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | | | - Richard Berry
- Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia
| | - Mary Carrington
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
- Basic Science Program, HLA Immunogenetics Section, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Marcus Altfeld
- Research Department Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
- German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany.
| |
Collapse
|
|
16
|
Wei L, Pavlovic V, Bansal AT, Chen X, Foster GR, He H, Kao JH, Lampertico P, Liaw YF, Motoc A, Papatheodoridis GV, Piratvisuth T, Plesniak R, Wat C. Genetic variation in FCER1A predicts peginterferon alfa-2a-induced hepatitis B surface antigen clearance in East Asian patients with chronic hepatitis B. J Viral Hepat 2019; 26:1040-1049. [PMID: 30972912 DOI: 10.1111/jvh.13107] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 02/06/2019] [Accepted: 03/14/2019] [Indexed: 12/13/2022]
Abstract
In a multicentre, genome-wide association study to identify host genetic factors associated with treatment response in adult chronic hepatitis B patients, genotype data were obtained by microarray analysis from 1669 patients who received peginterferon alfa-2a for ≥ 24 weeks with/without a nucleos(t)ide analog. Treatment response was assessed at least 24 weeks post-treatment, using serological and/or virological endpoints. Thirty-six single-marker analyses and a gene-by-gene analysis were conducted. No single nucleotide polymorphisms (SNPs) achieved genome-wide significance (P < 5 × 10-8 ) in single-marker analyses, but suggestive associations (P < 1 × 10-5 ) were identified for 116 SNPs. In gene-by-gene analyses, one gene, FCER1A (rs7549785), reached genome-wide significance (P = 2.65 × 10-8 ) in East Asian patients for hepatitis B surface antigen (HBsAg) clearance, with a moderate effect size (odds ratio = 4.74). Eleven of 44 carriers (25%) of the A allele at rs7549785 achieved HBsAg clearance compared with 69/1051 (7%) noncarriers. FCER1A encodes the alpha subunit of the immunoglobulin E receptor. In a post hoc analysis of a homogenous patient subset, the strongest intragenic association was for rs7712322 (POLR3G, P = 7.21 × 10-7 ). POLR3G encodes the G subunit of the polymerase (RNA) III enzyme, involved in sensing and limiting infection by intracellular bacteria and DNA viruses, and as a DNA sensor in innate immune responses. FCER1A (rs7549785) and possibly POLR3G (rs7712322) are shown to be associated with peginterferon alfa-2a response in adult patients with chronic hepatitis B. Independent confirmation of these findings is warranted (clinicaltrials.gov number NCT01855997).
Collapse
Affiliation(s)
- Lai Wei
- Peking University People's Hospital, Beijing, China.,Peking University Hepatology Institute, Beijing, China
| | | | | | | | - Graham R Foster
- Queen Mary's University of London, Bart's and The London School of Medicine, London, UK
| | - Hua He
- Roche Products Ltd, Welwyn Garden City, UK
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Pietro Lampertico
- AM & A Migliavacca Center for Liver Disease, Gastroenterology and Hepatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Adriana Motoc
- Infectious and Tropical Diseases Hospital 'Dr. Victor Babes', Bucharest, Romania
| | - George V Papatheodoridis
- Department of Gastroenterology, Medical School of National & Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Prince of Songkla University, Hat-Yai, Thailand
| | - Robert Plesniak
- Clinical Department Of Infectious Diseases, Faculty of Medicine, University of Rzeszów, Łańcut, Poland
| | | |
Collapse
|
|
17
|
Zhang Z, Wang C, Liu Z, Zou G, Li J, Lu M. Host Genetic Determinants of Hepatitis B Virus Infection. Front Genet 2019; 10:696. [PMID: 31475028 PMCID: PMC6702792 DOI: 10.3389/fgene.2019.00696] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 07/03/2019] [Indexed: 12/14/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is still a major health problem worldwide. Recently, a great number of genetic studies based on single nucleotide polymorphisms (SNPs) and genome-wide association studies have been performed to search for host determinants of the development of chronic HBV infection, clinical outcomes, therapeutic efficacy, and responses to hepatitis B vaccines, with a focus on human leukocyte antigens (HLA), cytokine genes, and toll-like receptors. In addition to SNPs, gene insertions/deletions and copy number variants are associated with infection. However, conflicting results have been obtained. In the present review, we summarize the current state of research on host genetic factors and chronic HBV infection, its clinical type, therapies, and hepatitis B vaccine responses and classify published results according to their reliability. The potential roles of host genetic determinants of chronic HBV infection identified in these studies and their clinical significance are discussed. In particular, HLAs were relevant for HBV infection and pathogenesis. Finally, we highlight the need for additional studies with large sample sizes, well-matched study designs, appropriate statistical methods, and validation in multiple populations to improve the treatment of HBV infection.
Collapse
Affiliation(s)
- Zhenhua Zhang
- Department of Infectious Diseases, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
- College of Pharmacy, Anhui Medical University, Hefei, China
| | - Changtai Wang
- Department of Infectious Diseases, the Affiliated Anqing Hospital of Anhui Medical University, Anqing, China
| | - Zhongping Liu
- Department of Infectious Diseases, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Guizhou Zou
- Department of Infectious Diseases, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jun Li
- College of Pharmacy, Anhui Medical University, Hefei, China
| | - Mengji Lu
- Institute of Virology, University Hospital of Duisburg-Essen, Essen, Germany
| |
Collapse
|
|
18
|
Koukoulioti E, Fischer J, Schott E, Fülöp B, Heyne R, Berg T, van Bömmel F. Association of HLA-DPA1 and HLA-DPB1 polymorphisms with spontaneous HBsAg seroclearance in Caucasians. Liver Int 2019; 39:646-654. [PMID: 30471179 DOI: 10.1111/liv.14008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 10/11/2018] [Accepted: 11/07/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Acute hepatitis B virus (HBV) infections may clear spontaneously or become chronic and run through different phases. The single nucleotide polymorphisms (SNPs) rs3077, rs9277535 and rs9277534 within the human leucocyte antigen (HLA)-DP gene have been found to be associated with HBV susceptibility and persistence in Asians. However, evidence for the influence of these variants in Caucasians has been limited so far. The aim of our study was to investigate the impact of these polymorphisms on the outcome of HBV infections in a large Caucasian population. METHODS In this case-control study, we retrospectively analysed 1111 Caucasian individuals, including 618 with chronic HBV infections (CHB), 239 with spontaneous HBsAg seroclearance (SC) and 254 healthy controls (HC). The rs3077, rs9277535 and rs9277534 SNPs were genotyped by a polymerase chain reaction from blood samples and melting curve analysis. RESULTS A significant difference in the allele distributions was observed only for the rs3077 SNP between the HC and the CHB group as well as between the SC and CHB groups. The rs3077-C allele was associated with a lower probability for spontaneous HBsAg seroclearance in comparison with the rs3077-T allele (OR 0.704, 95% CI 0.509-0.974; P = 0.033). No association of the three SNPs with the stages of chronic HBV infection was found. CONCLUSION This is the first study demonstrating an association of the rs3077-T allele with spontaneous HBsAg seroclearance in Caucasians. Further studies are needed to elucidate the role of HLA-DP variants in disease pathogenesis and their potential role for individualized disease management.
Collapse
Affiliation(s)
- Eleni Koukoulioti
- Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital Leipzig, Leipzig, Germany
| | - Janett Fischer
- Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital Leipzig, Leipzig, Germany
| | - Eckart Schott
- Department of Internal Medicine II, HELIOS Hospital Emil von Behring, Berlin, Germany
| | - Balazs Fülöp
- Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital Leipzig, Leipzig, Germany.,Department of Internal Medicine and Gastroenterology, HELIOS Hospital Berlin-Buch, Berlin, Germany
| | - Renate Heyne
- Department of Internal Medicine and Gastroenterology, HELIOS Hospital Berlin-Buch, Berlin, Germany
| | - Thomas Berg
- Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital Leipzig, Leipzig, Germany
| | - Florian van Bömmel
- Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital Leipzig, Leipzig, Germany
| |
Collapse
|
|
19
|
O'Brien TR, Yang HI, Groover S, Jeng WJ. Genetic Factors That Affect Spontaneous Clearance of Hepatitis C or B Virus, Response to Treatment, and Disease Progression. Gastroenterology 2019; 156:400-417. [PMID: 30287169 DOI: 10.1053/j.gastro.2018.09.052] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Revised: 09/21/2018] [Accepted: 09/24/2018] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) and hepatitis B virus (HBV) infections can lead to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Over the past decade, studies of individuals infected with these viruses have established genetic associations with the probability of developing a chronic infection, risk of disease progression, and likelihood of treatment response. We review genetic and genomic methods that have been used to study risk of HBV and HCV infection and patient outcomes. For example, genome-wide association studies have linked a region containing the interferon lambda genes to spontaneous and treatment-induced clearance of HCV. We review the genetic variants associated with HCV and HBV infection, and how these variants affect specific expression or activities of their products. Further studies of these variants could provide insights into risk factors for and mechanisms of chronic infection and disease progression, as well as new strategies for treatment.
Collapse
Affiliation(s)
- Thomas R O'Brien
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Sarah Groover
- Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, Oklahoma
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Liver Research Unit, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
| |
Collapse
|
|
20
|
Riazalhosseini B, Mohamed Z, Apalasamy YD, Shafie NS, Mohamed R. Interleukin-6 gene variants are associated with reduced risk of chronicity in hepatitis B virus infection in a Malaysian population. Biomed Rep 2018; 9:213-220. [PMID: 30271596 DOI: 10.3892/br.2018.1126] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 06/29/2018] [Indexed: 02/06/2023] Open
Abstract
Interleukin-6 (IL-6) is a cytokine with a critical role in regulating the immune response to infectious disease. Studies have indicated that polymorphisms in the IL-6 gene may be linked to hepatitis B virus (HBV) infection. The purpose of the present study was to examine the association among IL-6 SNPs and haplotypes with HBV infection risk in a Malaysian population. A total of 1,246 Malaysian subjects with and without chronic hepatitis B were recruited for this study. Three IL-6 polymorphisms (rs2069837, rs1800796 and rs2066992) were genotyped using a Sequenom MassARRAY® platform. The results suggested that GC and CC genotypes of rs1800796 as well as GT and TT genotypes of rs2066992 were associated with protection against HBV infection (P<0.001). Furthermore, haplotypes GG and CT exhibited a significant association with protection against HBV (P=0.003 and =0.005, respectively); and haplotypes GG and CT exhibited a significant association with clearance of HBV infection (P=0.035 and =0.037, respectively). The present study indicates that two IL-6 SNPs (rs1800796 and rs2066992) are associated with clearance of chronic HBV or protection against HBV infection at allelic, genotypic and haplotypic levels.
Collapse
Affiliation(s)
- Behnaz Riazalhosseini
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia
| | - Zahurin Mohamed
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia
| | - Yamunah Devi Apalasamy
- Social Wellbeing Research Centre, Faculty of Economics and Administration, University of Malaya, Kuala Lumpur 50603, Malaysia
| | - Noor Shafila Shafie
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia
| | - Rosmawati Mohamed
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia
| |
Collapse
|
|
21
|
Akcay IM, Katrinli S, Ozdil K, Doganay GD, Doganay L. Host genetic factors affecting hepatitis B infection outcomes: Insights from genome-wide association studies. World J Gastroenterol 2018; 24:3347-3360. [PMID: 30122875 PMCID: PMC6092584 DOI: 10.3748/wjg.v24.i30.3347] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 05/29/2018] [Accepted: 06/25/2018] [Indexed: 02/06/2023] Open
Abstract
The clinical outcome of Hepatitis B Virus (HBV) infection depends on the success or failure of the immune responses to HBV, and varies widely among individuals, ranging from asymptomatic self-limited infection, inactive carrier state, chronic hepatitis, cirrhosis, hepatocellular carcinoma, to liver failure. Genome-wide association studies (GWAS) identified key genetic factors influencing the pathogenesis of HBV-related traits. In this review, we discuss GWAS for persistence of HBV infection, antibody response to hepatitis B vaccine, and HBV-related advanced liver diseases. HBV persistence is associated with multiple genes with diverse roles in immune mechanisms. The strongest associations are found within the classical human leukocyte antigen (HLA) genes, highlighting the central role of antigen presentation in the immune response to HBV. Associated variants affect both epitope binding specificities and expression levels of HLA molecules. Several other susceptibility genes regulate the magnitude of adaptive immune responses, determining immunity vs tolerance. HBV persistence and nonresponse to vaccine share the same risk variants, implying overlapping genetic bases. On the other hand, the risk variants for HBV-related advanced liver diseases are largely different, suggesting different host-virus dynamics in acute vs chronic HBV infections. The findings of these GWAS are likely to pave the way for developing more effective preventive and therapeutic interventions by personalizing the management of HBV infection.
Collapse
Affiliation(s)
- Izzet Mehmet Akcay
- Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul 34469, Turkey
| | - Seyma Katrinli
- Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul 34469, Turkey
| | - Kamil Ozdil
- Department of Gastroenterology and Hepatology, Umraniye Teaching and Research Hospital, Istanbul 34764, Turkey
| | - Gizem Dinler Doganay
- Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul 34469, Turkey
| | - Levent Doganay
- Department of Gastroenterology and Hepatology, Umraniye Teaching and Research Hospital, Istanbul 34764, Turkey
| |
Collapse
|
|
22
|
Lai MW, Hsu CW, Lin CL, Chien RN, Lin WR, Chang CS, Liang KH, Yeh CT. Multiple doses of hepatitis B recombinant vaccine for chronic hepatitis B patients with low surface antigen levels: a pilot study. Hepatol Int 2018; 12:456-464. [PMID: 30088198 DOI: 10.1007/s12072-018-9890-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 07/21/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Seroclearance of hepatitis B surface antigen (HBsAg) has been rarely achieved in the treatment of chronic hepatitis B (CHB) patients. We administered HBsAg-based recombinant vaccine in patients with low HBsAg concentrations. METHODS Twenty hepatitis B e antigen-negative patients, with HBsAg < 1000 IU/ml, were enrolled. Vaccines were administered every 8 weeks for 48 weeks (seven doses). HBsAg levels and anti-HBs were assayed longitudinally until 48 weeks post-vaccination. HLA genotyping and cDNA microarray were performed to search for response predictors. RESULTS Nineteen patients completed the study. At the end of vaccination, HBsAg declined significantly (Δ = - 0.27 ± 0.49 log IU/ml, p = 0.0005). The annual decline rate was significantly greater than that of an age-, gender-, and baseline HBsAg-matched control group (Δ = - 0.18 ± 0.46 versus + 0.11 ± 0.42 log IU/ml/year; p = 0.0229). Two patients achieved HBsAg seroclearance. Fourteen had significant HBsAg decline (Δ = - 0.64 ± 0.88 log IU/ml). No significant adverse events occurred during the trial. cDNA microarray identified the top up- and down-regulated genes in responders as HLA-DQ and HLA-DMB, respectively. HLA genotyping identified HLA-DQB1*04, HLA-DRB1*04, and HLA-B*40 as predictors for non-response (p = 0.0499, 0.0152, and 0.0314, respectively). CONCLUSIONS In low-level HBsAg CHB patients, serial HBsAg-based vaccinations were safe, resulting in significant HBsAg decline. HLA gene expression and genotypes played a role in vaccine responsiveness (ClinicalTrials.gov Identifier: NCT01817725).
Collapse
Affiliation(s)
- Ming-Wei Lai
- Division of Pediatric Gastroenterology, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan.,Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan.,Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Chao-Wei Hsu
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan.,Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Chih-Lang Lin
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan.,Liver Research Unit, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Rong-Nan Chien
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan.,Liver Research Unit, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Wey-Ran Lin
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan.,Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Chi-Sheng Chang
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan
| | - Kung-Hao Liang
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan.,Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan. .,Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan City, Taiwan.
| |
Collapse
|
|
23
|
Arciero E, Kraaijenbrink T, Asan, Haber M, Mezzavilla M, Ayub Q, Wang W, Pingcuo Z, Yang H, Wang J, Jobling MA, van Driem G, Xue Y, de Knijff P, Tyler-Smith C. Demographic History and Genetic Adaptation in the Himalayan Region Inferred from Genome-Wide SNP Genotypes of 49 Populations. Mol Biol Evol 2018; 35:1916-1933. [PMID: 29796643 PMCID: PMC6063301 DOI: 10.1093/molbev/msy094] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
We genotyped 738 individuals belonging to 49 populations from Nepal, Bhutan, North India, or Tibet at over 500,000 SNPs, and analyzed the genotypes in the context of available worldwide population data in order to investigate the demographic history of the region and the genetic adaptations to the harsh environment. The Himalayan populations resembled other South and East Asians, but in addition displayed their own specific ancestral component and showed strong population structure and genetic drift. We also found evidence for multiple admixture events involving Himalayan populations and South/East Asians between 200 and 2,000 years ago. In comparisons with available ancient genomes, the Himalayans, like other East and South Asian populations, showed similar genetic affinity to Eurasian hunter-gatherers (a 24,000-year-old Upper Palaeolithic Siberian), and the related Bronze Age Yamnaya. The high-altitude Himalayan populations all shared a specific ancestral component, suggesting that genetic adaptation to life at high altitude originated only once in this region and subsequently spread. Combining four approaches to identifying specific positively selected loci, we confirmed that the strongest signals of high-altitude adaptation were located near the Endothelial PAS domain-containing protein 1 and Egl-9 Family Hypoxia Inducible Factor 1 loci, and discovered eight additional robust signals of high-altitude adaptation, five of which have strong biological functional links to such adaptation. In conclusion, the demographic history of Himalayan populations is complex, with strong local differentiation, reflecting both genetic and cultural factors; these populations also display evidence of multiple genetic adaptations to high-altitude environments.
Collapse
Affiliation(s)
- Elena Arciero
- The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom
| | - Thirsa Kraaijenbrink
- Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Asan
- BGI-Shenzhen, Shenzhen, China
| | - Marc Haber
- The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom
| | - Massimo Mezzavilla
- The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom
- Division of Experimental Genetics, Sidra Medical and Research Center, Doha, Qatar
| | - Qasim Ayub
- The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom
- Tropical Medicine and Biology Multidisciplinary Platform, Monash University Malaysia Genomics Facility, Selangor Darul Ehsan, Malaysia
- School of Science, Monash University Malaysia, Selangor Darul Ehsan, Malaysia
| | | | - Zhaxi Pingcuo
- The Third People’s Hospital of the Tibet Autonomous Region, Lhasa, China
| | - Huanming Yang
- BGI-Shenzhen, Shenzhen, China
- James D. Watson Institute of Genome Science, Hangzhou, China
| | - Jian Wang
- BGI-Shenzhen, Shenzhen, China
- James D. Watson Institute of Genome Science, Hangzhou, China
| | - Mark A Jobling
- Department of Genetics & Genome Biology, University of Leicester, Leicester, United Kingdom
| | | | - Yali Xue
- The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom
| | - Peter de Knijff
- Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Chris Tyler-Smith
- The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom
| |
Collapse
|
|
24
|
Yao YF, Zhou YY, Xu HL. First identification of the MHC-DPB2 alleles in the rhesus macaques (Macaca mulatta). HLA 2018; 92:188-190. [PMID: 29790277 DOI: 10.1111/tan.13255] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 02/22/2018] [Accepted: 03/06/2018] [Indexed: 11/26/2022]
Abstract
We report here the identification of three MHC-DPB2 alleles in the rhesus macaques (Macaca mulatta).
Collapse
Affiliation(s)
- Y F Yao
- College of Life Science, Sichuan Agricultural University, Ya'an, China.,College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Y Y Zhou
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - H L Xu
- College of Life Science, Sichuan Agricultural University, Ya'an, China
| |
Collapse
|
|
25
|
Su TH, Yang HC, Tseng TC, Liou JM, Liu CH, Chen CL, Chen PJ, Chen DS, Liu CJ, Kao JH. Distinct Relapse Rates and Risk Predictors After Discontinuing Tenofovir and Entecavir Therapy. J Infect Dis 2018; 217:1193-1201. [PMID: 29300980 DOI: 10.1093/infdis/jix690] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Accepted: 12/29/2017] [Indexed: 01/02/2025] Open
Abstract
BACKGROUND We investigated the patterns and predictors for virological relapse (VR), clinical relapse (CR), and sustained clinical response (SCR) and the outcomes of retreatment after nucleos(t)ide analogue (NUC) therapy discontinuation. METHODS Patients with chronic hepatitis B who were discontinuing NUC therapy were prospectively enrolled. Viral and host predictors of relapse were evaluated, including hepatitis B virus (HBV) surface antigen (HBsAg) level, anti-HBV core antibody level, and presence of single-nucleotide polymorphisms in the genes encoding the receptors NTCP (rs2296651) and CTLA4 (rs231775) and in the 3' untranslated regions of the genes encoding HLA-DPA1 (rs3077) and HLA-DPB1 (rs9277535); posttherapy predictors of relapse were also investigated. Information about NUC retreatment and outcomes were recorded. RESULTS Overall, 100 patients discontinuing 3-year entecavir (ETV) or tenofovir (TDF) therapy were enrolled. Patients discontinuing TDF exhibited significantly higher rates of VR (52.9% vs 6.1%; P < .001) and CR (15.2% vs. 1.5%, P = .007) at 3 months than those discontinuing ETV, but relapse rates at 12 months were comparable. The end-of-therapy HBsAg levels predicted VR (hazard ratio [HR], 1.62; 95% confidence interval [CI], 1.19-2.21), CR (HR, 1.78; 95% CI, 1.13-2.81), and SCR (OR, 0.57; 95% CI, .35-.94). The CTLA4 (rs231775) non-GG genotype predicted VR (HR, 1.74; 95% CI, 1.01-3.00) and CR (HR, 2.06; 95% CI, 1.04-4.11), while the HLA-DPA1 (rs3077) AA genotype predicted SCR (OR, 10.84; 95% CI, 1.12-105). The HBV DNA 1 month after NUC treatment cessation was an early predictor of subsequent relapse. CONCLUSIONS Discontinuation of tenofovir disoproxil fumarate treatment rather than entecavir treatment is associated with earlier relapse, and NUC-specific posttherapy monitoring is necessary.
Collapse
Affiliation(s)
- Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Hung-Chih Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Tai-Chung Tseng
- Department of Internal Medicine, National Taiwan University Hospital, Jin-shan Branch, New Taipei City, Taiwan
| | - Jyh-Ming Liou
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chen-Hua Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chi-Ling Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Pei-Jer Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ding-Shinn Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| |
Collapse
|
|
26
|
Li H, Chen J, Zhang R, Xu R, Zhang Z, Ren L, Yang Q, Tian Y, Li D. Single nucleotide polymorphisms in ZNF208 are associated with increased risk for HBV in Chinese people. Oncotarget 2017; 8:112451-112459. [PMID: 29348838 PMCID: PMC5762523 DOI: 10.18632/oncotarget.19669] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2017] [Accepted: 05/22/2017] [Indexed: 12/26/2022] Open
Abstract
Single nucleotide polymorphisms (SNPs) in ZNF208 may be associated with susceptibility to Hepatitis B virus (HBV). In the current study, we analyzed the association between ZNF208 SNPs and risk of HBV in 242 HBV patients and 300 healthy subjects from the Xi'an area of Chinese Han Population. Of the five SNPs examined, rs2188971 (OR: 1.36, 95% CI: 1.04-1.76, P = 0.022), rs8103163 (OR: 1.40, 95% CI: 1.08-1.82, P = 0.010) and rs7248488 (OR: 1.38, 95% CI: 1.07-1.79, P = 0.014) were correlated with HBV susceptibility based on Chi-square tests. After the P-values were adjusted by Bonferroni correction, there only rs8103163 (P = 0.050) was slightly with increased HBV risk. Additionally, haplotype Ars2188972Trs2188971Ars8103163Ars7248488 (OR = 1.42; 95% C I, 1.10-1.85; P = 0.008) was found to increase susceptibility of suffering from HBV. These findings suggest that ZNF208 polymorphisms may contribute to the development of HBV.
Collapse
Affiliation(s)
- Hengxin Li
- Xi'an Center for Disease Control and Prevention, Xi'an, Shaanxi 710054, China
| | - Jun Chen
- Department of Pharmacy, The Ankang Central Hospital, Ankang, Shaanxi 725000, China
| | - RuiZhi Zhang
- Department of Stomatology, The Ankang Central Hospital, Ankang, Shaanxi 725000, China
| | - Ran Xu
- Department of Stomatology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Zhe Zhang
- Department of Stomatology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Le Ren
- Department of Stomatology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Qi Yang
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.,Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Yumei Tian
- Xi'an Mental Health Center, Xi'an, Shaanxi 710061, China
| | - Daxu Li
- Department of Stomatology, The Ankang Central Hospital, Ankang, Shaanxi 725000, China
| |
Collapse
|
|
27
|
Li W, Shen X, Fu B, Guo C, Liu Y, Ye Y, Sun R, Li J, Tian Z, Wei H. KIR3DS1/HLA-B Bw4-80Ile Genotype Is Correlated with the IFN-α Therapy Response in hepatitis B e antigen-Positive Chronic Hepatitis B. Front Immunol 2017; 8:1285. [PMID: 29075265 PMCID: PMC5641573 DOI: 10.3389/fimmu.2017.01285] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 09/25/2017] [Indexed: 12/17/2022] Open
Abstract
To date, several on-treatment-level virological and serological indices that may predict the response to interferon alpha (IFN-α) have been reported. However, no effective predictors, such as drug–response genes, that can be detected before administration of anti-hepatitis B virus (HBV) therapy with IFN-α, have been found. In the diverse range of chronic viral infection, genes that affect human immunity play important roles in understanding host and viral co-evolution. Killer-cell immunoglobulin-like receptors (KIRs), which are highly polymorphic at the allele and haplotype levels, participate in the antiviral function of natural killer (NK) cells via fine-tuning inhibition and activation of NK-cell responses that occur when the NK cells interact with human leukocyte antigen (HLA) class I molecules on target cells. For each individual, the pairing of KIR and HLA ligand is genetically determined. To investigate whether a particular KIR and HLA repertoire influences the risk of HBV infection and response to IFN-α treatment for chronic hepatitis B (CHB), we genotyped the KIRs and HLA ligands of 119 hepatitis B e antigen (HBeAg)-positive CHB patients. These patients included 43 patients who achieved sustained response (SR) induced by IFN-α treatment for 48 weeks, 76 patients who achieved no response (NR), and 96 healthy subjects as controls. SR was defined as HBeAg loss with HBV DNA < 2,000 IU/ml and alanine aminotransferase normalization at 24 weeks posttreatment (week 72). In this study, we showed that activating KIR genes were less prevalent in Han Chinese, especially in Han Chinese with CHB, than in Caucasians. Furthermore, the KIR3DS1 gene, in combination with HLA-B Bw4-80Ile, strongly influenced the therapeutic outcomes for CHB patients who were treated with IFN-α. The frequency of the combination of genes encoding KIR3DS1 and HLA-B Bw4-80Ile was higher in patients who had a sustained treatment response than in patients who had NR [35.3 versus 1.3%; odds ratio (OR) = 19.85; P = 0.0008]. Activating KIR3DS1 and HLA-B Bw4-80Ile synergistically predicted SR to IFN-α for HBeAg-positive CHB patients. Genotyping for the KIR3DS1 gene and the HLA-B Bw4-80Ile allele might help physicians choose the optimal candidates for anti-HBV treatment with IFN-α.
Collapse
Affiliation(s)
- Wenting Li
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Xiaokun Shen
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Binqing Fu
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Institute of Immunology, University of Science and Technology of China, Hefei, China.,Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, China
| | - Chuang Guo
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Yanyan Liu
- Department of Infectious Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ying Ye
- Department of Infectious Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Rui Sun
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Institute of Immunology, University of Science and Technology of China, Hefei, China.,Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, China
| | - Jiabin Li
- Department of Infectious Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhigang Tian
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Institute of Immunology, University of Science and Technology of China, Hefei, China.,Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, China
| | - Haiming Wei
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, Institute of Immunology, University of Science and Technology of China, Hefei, China.,Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, China
| |
Collapse
|
|
28
|
Trinks J, Nishida N, Hulaniuk ML, Caputo M, Tsuchiura T, Marciano S, Haddad L, Blejer J, Bartoli S, Ameigeiras B, Frías SE, Vistarini C, Heinrich F, Remondegui C, Ceballos S, Echenique G, Charre Samman M, D'Amico C, Rojas A, Martínez A, Ridruejo E, Fernández RJ, Burgos Pratx L, Salamone H, Nuñez F, Galdame O, Gadano A, Corach D, Sugiyama M, Flichman D, Tokunaga K, Mizokami M. Role of HLA-DP and HLA-DQ on the clearance of hepatitis B virus and the risk of chronic infection in a multiethnic population. Liver Int 2017; 37:1476-1487. [PMID: 28267888 DOI: 10.1111/liv.13405] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 02/27/2017] [Indexed: 12/27/2022]
Abstract
BACKGROUND & AIMS HBV infection exhibits geographical variation in its distribution in South America. While HBV rates are low in central Argentina, the north-western region exhibits intermediate HBV rates. Unfortunately, the reasons that could explain this difference are still unknown. METHODS A total of 1440 Argentines were recruited and grouped into HBV patients, HBV-resolved individuals and healthy controls. Genetic ancestry was assessed by analysis of biparental lineages and ancestry autosomal typing. SNPs of HLA-DPA1 (rs3077), HLA-DPB1 (rs9277542), HLA-DQB1 (rs2856718) and HLA-DQB2 (rs7453920) were determined, and HBV genotyping was performed by phylogenetic analysis in HBV patients. RESULTS Native American ancestry prevailed in the north-western region when compared with central Argentina (P<.0001). However, no differences were observed among the three groups of each region. The distribution of HBV genotypes revealed significant differences (P<.0001). Three SNPs (rs3077, rs9277542 and rs7453920) showed a significant association with protection against chronic HBV and viral clearance in both regions. The remaining SNP showed a significant association with susceptibility to chronic HBV. The frequency rates of rs3077-T, related to protection against chronic HBV and viral clearance, were lower in north-western Argentina when compared with central Argentina. The same uneven frequency rates were observed for SNP rs9277542. CONCLUSIONS This is the first study addressing the associations between the HLA-DP and HLA-DQ loci and the protection against chronic HBV and viral clearance in a multiethnic South American population. The uneven distribution of HLA-DP and HLA-DQ supports the HBV epidemiological differences observed in these two regions of Argentina with dissimilar ancestry genetic background.
Collapse
Affiliation(s)
- Julieta Trinks
- Basic Sciences and Experimental Medicine Institute (ICBME), University Institute of the Italian Hospital of Buenos Aires, Buenos Aires, Argentina.,Scientific and Technological Research Council (CONICET), Buenos Aires, Argentina
| | - Nao Nishida
- Department of Hepatic Disease, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan.,Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - María Laura Hulaniuk
- Basic Sciences and Experimental Medicine Institute (ICBME), University Institute of the Italian Hospital of Buenos Aires, Buenos Aires, Argentina
| | - Mariela Caputo
- Scientific and Technological Research Council (CONICET), Buenos Aires, Argentina.,Genetic Fingerprints Unit, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
| | - Takayo Tsuchiura
- Department of Hepatic Disease, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
| | - Sebastián Marciano
- Hepatology Unit, Italian Hospital of Buenos Aires, Buenos Aires, Argentina
| | - Leila Haddad
- Hepatology Unit, Italian Hospital of Buenos Aires, Buenos Aires, Argentina
| | | | - Sonia Bartoli
- Hemotherapy Unit, "Pablo Soria" Hospital, San Salvador de Jujuy, Argentina
| | - Beatriz Ameigeiras
- Hepatology Unit, "José María Ramos Mejía" General Hospital, Buenos Aires, Argentina
| | - Silvia E Frías
- Hepatology Unit, "José María Ramos Mejía" General Hospital, Buenos Aires, Argentina
| | - Cecilia Vistarini
- Hepatology Unit, "José María Ramos Mejía" General Hospital, Buenos Aires, Argentina
| | | | - Carlos Remondegui
- Infectology and Tropical Medicine Unit, "San Roque" Hospital, San Salvador de Jujuy, Argentina
| | - Susana Ceballos
- Infectology and Tropical Medicine Unit, "San Roque" Hospital, San Salvador de Jujuy, Argentina
| | - Gustavo Echenique
- "Nuestra Señora del Rosario" Clinic, San Salvador de Jujuy, Argentina
| | | | - Claudia D'Amico
- Ambulatory Medical Specialities Center (CEMA), Mar del Plata, Argentina
| | - Amalia Rojas
- Ambulatory Medical Specialities Center (CEMA), Mar del Plata, Argentina
| | - Alfredo Martínez
- Center for Medical Education and Clinical Research "Norberto Quirno" (CEMIC), Buenos Aires, Argentina
| | - Ezequiel Ridruejo
- Center for Medical Education and Clinical Research "Norberto Quirno" (CEMIC), Buenos Aires, Argentina
| | | | - Leandro Burgos Pratx
- Transfusional Medicine Unit, Italian Hospital of Buenos Aires, Buenos Aires, Argentina
| | - Horacio Salamone
- Transfusional Medicine Unit, Italian Hospital of Buenos Aires, Buenos Aires, Argentina
| | - Félix Nuñez
- Transfusional Medicine Unit, Italian Hospital of Buenos Aires, Buenos Aires, Argentina
| | - Omar Galdame
- Hepatology Unit, Italian Hospital of Buenos Aires, Buenos Aires, Argentina
| | - Adrián Gadano
- Hepatology Unit, Italian Hospital of Buenos Aires, Buenos Aires, Argentina
| | - Daniel Corach
- Scientific and Technological Research Council (CONICET), Buenos Aires, Argentina.,Genetic Fingerprints Unit, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
| | - Masaya Sugiyama
- Department of Hepatic Disease, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
| | - Diego Flichman
- Scientific and Technological Research Council (CONICET), Buenos Aires, Argentina.,Virology Department, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
| | - Katsushi Tokunaga
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masashi Mizokami
- Department of Hepatic Disease, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
| |
Collapse
|
|
29
|
Okada Y, Uno N, Sato S, Mori S, Sasaki D, Kaku N, Kosai K, Morinaga Y, Hasegawa H, Yanagihara K. Strong influence of human leukocyte antigen-DP variants on response to hepatitis B vaccine in a Japanese population. Vaccine 2017; 35:5662-5665. [PMID: 28882445 DOI: 10.1016/j.vaccine.2017.08.045] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 08/14/2017] [Accepted: 08/19/2017] [Indexed: 12/17/2022]
Abstract
Genome-wide association studies (GWASs) have reported that human leukocyte antigen (HLA) variants are associated with chronic hepatitis B, spontaneous hepatitis B virus (HBV) clearance, and response to hepatitis B vaccine. Single nucleotide polymorphisms (SNPs) in HLA-DP (rs9277535 and rs3077) and HLA-DQ (rs2856718 and rs7453920) have been repeatedly associated with chronic hepatitis B and spontaneous HBV clearance. However, the data on the SNPs associated with response to hepatitis B vaccine are inconclusive. The objective of this study was to determine whether these four HLA SNPs that have been identified as risk loci for chronic HBV infection are associated with response to hepatitis B vaccine in a Japanese population. We enrolled 278 medical students who received hepatitis B vaccination and measured anti-hepatitis B surface (HBs) antibody titers 1month after a three-dose vaccination series. We found that rs9277535 and rs3077 in HLA-DP were strongly associated with response to hepatitis B vaccine (odds ratio [OR]=0.31 and 0.32, P=0.004 and 0.010, respectively). These two SNPs were significantly associated with anti-HBs titers in an allele-dependent manner. On the other hand, rs2856718 and rs7453920 in HLA-DQ were not associated with response to hepatitis B vaccine. These results indicate that rs9277535 and rs3077 in HLA-DP are the major determinants of response to hepatitis B vaccine, whereas rs2856718 and rs7453920 in HLA-DQ have little effect on the immune response to hepatitis B vaccine.
Collapse
Affiliation(s)
- Yuya Okada
- Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Naoki Uno
- Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
| | - Shuntaro Sato
- Clinical Research Center, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Sayaka Mori
- Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Daisuke Sasaki
- Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Norihito Kaku
- Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Kosuke Kosai
- Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Yoshitomo Morinaga
- Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Hiroo Hasegawa
- Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Katsunori Yanagihara
- Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| |
Collapse
|
|
30
|
Hiramatsu K, Matsuda H, Nemoto T, Nosaka T, Saito Y, Naito T, Takahashi K, Ofuji K, Ohtani M, Suto H, Yasuda T, Hida Y, Kimura H, Soya Y, Nakamoto Y. Identification of novel variants in HLA class II region related to HLA DPB1 expression and disease progression in patients with chronic hepatitis C. J Med Virol 2017; 89:1574-1583. [PMID: 28332201 DOI: 10.1002/jmv.24814] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 03/01/2017] [Indexed: 02/06/2023]
Abstract
Recent genome-wide studies have demonstrated that HLA class II gene may play an important role in viral hepatitis. We studied genetic polymorphism and RNA expression of HLA class II genes in HCV-related liver diseases. The study was performed in groups consisting of 24 patients with HCV-related liver disease (12 of persistent normal ALT: PNALT group and 12 of advanced liver disease: ALD group) and 26 patients without HCV infection (control group). In PBMC samples, RNA expression of HLA class II genes (HLA-DPA1, DPB1, DQA1, DQB1, and DRB1) was analyzed by real-time RT-PCR. Furthermore, 22 single nucleotide polymorphisms (SNPs) in HLA class II gene and two SNPs in IL28B gene were genotyped by genetic analyzer (GENECUBE®). In expression analysis, only DPB1 level was significantly different. Mean expression level of DPB1gene in control group was 160.0, PNALT group 233.8, and ALD group 465.0 (P < 0.01). Of 24 SNPs, allele frequencies were statistically different in two SNPs (rs2071025 and rs3116996) between PNALT groups and ALD group (P < 0.01). In rs2071025, TT genotype was frequently detected in ALD group and expression level was significantly higher than the other genotypes (449.2 vs 312.9, P < 0.01). In rs3116996, TA or TT (non AA) genotype was frequently detected in ALD group and expression level was significantly higher than genotype AA (457.1 vs 220.9, P < 0.01). Genotyping and expression analysis in HLA class II gene revealed that two SNPs of HLA-DPB1 (rs2071025 and rs3116996) were significantly correlated to RNA expression and progression of HCV-related liver diseases.
Collapse
Affiliation(s)
- Katsushi Hiramatsu
- Faculty of Medical Sciences, Second Department of Internal Medicine, University of Fukui, Fukui, Japan
| | - Hidetaka Matsuda
- Faculty of Medical Sciences, Second Department of Internal Medicine, University of Fukui, Fukui, Japan
| | - Tomoyuki Nemoto
- Faculty of Medical Sciences, Second Department of Internal Medicine, University of Fukui, Fukui, Japan
| | - Takuto Nosaka
- Faculty of Medical Sciences, Second Department of Internal Medicine, University of Fukui, Fukui, Japan
| | - Yasushi Saito
- Faculty of Medical Sciences, Second Department of Internal Medicine, University of Fukui, Fukui, Japan
| | - Tatsushi Naito
- Faculty of Medical Sciences, Second Department of Internal Medicine, University of Fukui, Fukui, Japan
| | - Kazuto Takahashi
- Faculty of Medical Sciences, Second Department of Internal Medicine, University of Fukui, Fukui, Japan
| | - Kazuya Ofuji
- Faculty of Medical Sciences, Second Department of Internal Medicine, University of Fukui, Fukui, Japan
| | - Masahiro Ohtani
- Faculty of Medical Sciences, Second Department of Internal Medicine, University of Fukui, Fukui, Japan
| | - Hiroyuki Suto
- Faculty of Medical Sciences, Second Department of Internal Medicine, University of Fukui, Fukui, Japan
| | - Toshihiro Yasuda
- Faculty of Medical Sciences, Division of Medical Genetics and Biochemistry, University of Fukui, Fukui, Japan
| | - Yukio Hida
- Faculty of Medical Sciences, Department of Clinical Laboratories, University of Fukui, Fukui, Japan
| | - Hideki Kimura
- Faculty of Medical Sciences, Department of Clinical Laboratories, University of Fukui, Fukui, Japan
| | - Yoshihiro Soya
- Tsuruga Institute of Biotechnology, Toyobo Co., Ltd., Osaka, Japan
| | - Yasunari Nakamoto
- Faculty of Medical Sciences, Second Department of Internal Medicine, University of Fukui, Fukui, Japan
| |
Collapse
|
|
31
|
Cheng G, Yuan X, Wang F, Sun Q, Xin Q, Li K, Sun C, Lin Z, Luan Y, Xu Y, Li P, Kong F, Xu D. Association Between the Telomerase rs2736098_TT Genotype and a Lower Risk of Chronic Hepatitis B and Cirrhosis in Chinese Males. Clin Transl Gastroenterol 2017; 8:e79. [PMID: 28300824 PMCID: PMC5387758 DOI: 10.1038/ctg.2017.9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2016] [Accepted: 01/30/2017] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVES Chronic hepatitis B (CHB) is caused by infection of hepatitis B virus (HBV) and liver cirrhosis (LC) is its most common complication. The accumulated evidence indicates a genetic context of HBV infection phenotypes. Here we determine a potential association of CHB/LC with the genetic variant of telomerase reverse transcriptase (TERT), a key player in aging including immune-senescence. METHODS The study included 227 Chinese CHB patients and 315 sex/age-matched healthy controls. TERT rs2736098 and rs2736100 genotyping was performed using pre-designed TaqMan SNP genotyping assay kits. Leukocyte telomere length (LTL) was determined using quantitative PCR. RESULTS The rs2736098_CT/CC genotypes were significantly associated with risk of CHB compared to the TT one (OR 2.265, 95% CI 1.202-4.269, P=0.015). A similar association was also found in CHB patients with cirrhosis (CT/CC vs TT: OR 2.398, 95% CI 1.168-4.922, P=0.02). Further analyses showed that the rs2736098_TT genotype difference occurred between male controls and patients (P=0.008) and male CT/CC-carriers exhibited highly increased risk of CHB compared to male controls (CT+CC vs TT, OR 3.182, 95% CI 1.350-7.500, P=0.01). There was no difference in the rs2736100 variants between controls and CHB patients. LTL was not different between cases and controls. CONCLUSIONS The TERT rs2736098_TT genotype is associated with a lower CHB and LC risk in Chinese males, which may have implications in CHB pathogenesis and prevention.
Collapse
Affiliation(s)
- Guanghui Cheng
- Central Research Laboratory, The Second Hospital of Shandong University, Jinan, PR China
| | - Xiaotian Yuan
- Central Research Laboratory, The Second Hospital of Shandong University, Jinan, PR China
- Department of Medicine, Division of Hematology and Center for Molecular Medicine, Karolinska University Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Fang Wang
- Clinical Laboratory, The Second Hospital of Shandong University, Jinan, PR China
| | - Qing Sun
- Central Research Laboratory, The Second Hospital of Shandong University, Jinan, PR China
| | - Qian Xin
- Central Research Laboratory, The Second Hospital of Shandong University, Jinan, PR China
| | - Kailin Li
- Central Research Laboratory, The Second Hospital of Shandong University, Jinan, PR China
| | - Chao Sun
- Central Research Laboratory, The Second Hospital of Shandong University, Jinan, PR China
| | - Zhaomin Lin
- Central Research Laboratory, The Second Hospital of Shandong University, Jinan, PR China
| | - Yun Luan
- Central Research Laboratory, The Second Hospital of Shandong University, Jinan, PR China
| | - Yiteng Xu
- Central Research Laboratory, The Second Hospital of Shandong University, Jinan, PR China
| | - Ping Li
- School of Nursing, Shandong University, Jinan, PR China
| | - Feng Kong
- Central Research Laboratory, The Second Hospital of Shandong University, Jinan, PR China
| | - Dawei Xu
- Central Research Laboratory, The Second Hospital of Shandong University, Jinan, PR China
- Department of Medicine, Division of Hematology and Center for Molecular Medicine, Karolinska University Institutet and Karolinska University Hospital, Stockholm, Sweden
| |
Collapse
|
|
32
|
Akgöllü E, Bilgin R, Akkız H, Ülger Y, Kaya BY, Karaoğullarından Ü, Arslan YK. Association between chronic hepatitis B virus infection and HLA-DP gene polymorphisms in the Turkish population. Virus Res 2017; 232:6-12. [PMID: 28119119 DOI: 10.1016/j.virusres.2017.01.017] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2016] [Revised: 01/17/2017] [Accepted: 01/17/2017] [Indexed: 12/23/2022]
Abstract
AIM Hepatitis B virus (HBV) affects approximately 360 million people worldwide. 10-15% of patients with chronic HBV develop liver cirrhosis (LC), liver failure and hepatocellular carcinoma (HCC). Chronic HBV infection or HBV clearance is influenced by both viral and host factors. In genome-wide association studies (GWAS), the human leukocyte antigen (HLA) gene polymorphisms rs3077 and rs9277535 were identified to be associated with chronic hepatitis B. HLA genes have been linked to immune response to infectious agents. Genetic variants in HLA genes influence HLA mRNA expression which might also affect antigen presentation. We evaluated the association between HLA gene polymorphisms and the risk for persistent HBV infection. METHODS In the current study, HLA gene polymorphisms were investigated in a case-control study of 294 chronic HBV patients and 234 persons with HBV natural clearance by using a real-time polymerase chain reaction (RT-PCR). RESULTS The results showed that rs9277535 allele frequency is associated with HBV infection in the Turkish subjects examined (P=0.048). However, no association was found for rs3077. Additionally, the AG haplotype block showed a protective effect against the risk of persistent HBV infection (for the rs3077A/rs9277535G, OR=0.52; 95% 0.34-0.80, P=0.003). CONCLUSIONS Our results, for the first time, demonstrate that HLA-DPB1 gene rs9277535A allele has a major effect on the risk of persistent HBV infection. We suggest that further independent studies are necessary to clarify the association of these polymorphisms with persistence or natural clearance of HBV infection in Caucasian populations.
Collapse
Affiliation(s)
- Ersin Akgöllü
- Çukurova University, Faculty of Medicine, Department of Gastroenterology, Adana, Turkey.
| | - Ramazan Bilgin
- Department of Chemistry, Arts and Science Faculty, Çukurova University, Adana, Turkey.
| | - Hikmet Akkız
- Çukurova University, Faculty of Medicine, Department of Gastroenterology, Adana, Turkey.
| | - Yakup Ülger
- Çukurova University, Faculty of Medicine, Department of Gastroenterology, Adana, Turkey.
| | - Berrin Yalınbaş Kaya
- Çukurova University, Faculty of Medicine, Department of Gastroenterology, Adana, Turkey.
| | - Ümit Karaoğullarından
- Çukurova University, Faculty of Medicine, Department of Gastroenterology, Adana, Turkey.
| | - Yusuf Kemal Arslan
- Çukurova University, Faculty of Medicine, Department of Biostatistics, Adana, Turkey.
| |
Collapse
|
|
33
|
Moudi B, Heidari Z, Mahmoudzadeh-Sagheb H. Impact of host gene polymorphisms on susceptibility to chronic hepatitis B virus infection. INFECTION GENETICS AND EVOLUTION 2016; 44:94-105. [DOI: 10.1016/j.meegid.2016.06.043] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 06/21/2016] [Accepted: 06/22/2016] [Indexed: 12/15/2022]
|
|
34
|
Fan J, Huang X, Chen J, Cai Y, Xiong L, Mu L, Zhou L. Host Genetic Variants in HLA Loci Influence Risk for Hepatitis B Virus Infection in Children. HEPATITIS MONTHLY 2016; 16:e37786. [PMID: 27795724 PMCID: PMC5070562 DOI: 10.5812/hepatmon.37786] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 06/27/2016] [Accepted: 06/29/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is a serious public health problem in China and worldwide. Mother-to-child transmission is one of HBV's main transmission routes in highly endemic regions. Genome-wide association studies (GWAS) identify single nucleotide polymorphisms (SNPs) at HLA loci as associated with HBV infection. However, the mechanisms of HBV perinatal transmission and breakthrough in children have not yet been clearly defined. OBJECTIVES We aimed to explore the association between SNPs at HLA loci and HBV infection and breakthrough in children. METHODS A total of 274 HBV-infected children and 353 controls were selected among children aged between 6 months and 12 years in China. Seven SNPs at HLA-DP and HLA-DQ loci were genotyped to analyze their association with HBV infection in children. RESULTS Alleles G in both HLA-DPA1 rs3077 and HLA-DPB1 rs9277535 were found to be significantly associated with HBV infection in children with odds ratios (OR) of 1.309 (95% CI 1.046 to 1.639) and 1.411 (95% CI 1.125 to 1.771), respectively. In addition, overdominant analysis found that the rs2281388 (HLA-DPB1) GA genotype and the rs9366816 (HLA-DPB2) TC genotype were related to HBV infection (rs2281388, OR = 1.422, 95% CI: 1.032-1.961; rs9366816, OR = 1.444, 95% CI: 1.045-1.994). Furthermore, this study highlighted that rs9277535 was also significantly associated with HBV breakthrough infection in children whose mothers were positive for hepatitis B surface antigen (HBsAg). CONCLUSIONS Our study confirmed that genetic variants in HLA-DPA1 and HLA-DPB1 loci have significant associations with HBV infection, especially with HBV breakthrough in children. This study provides insight into HBV infection in children and is valuable for the targeted management of, and control strategies for, this disease.
Collapse
Affiliation(s)
- Jie Fan
- Department of Epidemiology, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China
| | - Xin Huang
- Department of Epidemiology, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China
| | - Juan Chen
- Key Laboratory of Molecular Biology for Infectious Diseases, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yiling Cai
- Obstetrics and Gynecology Department, Chengdu Women and Children’s Central Hospital, Sichuan Province, China
| | - Lin Xiong
- Maternal and Child Health Hospital of Chongqing Yuzhong District, Chongqing, China
| | - Lihong Mu
- Department of Epidemiology, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China
- Corresponding Authors: Lihong Mu, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, School of Public Health and Management, Chongqing Medical University, Chongqing, China. Tel/Fax: +86-2368485008, E-mail: ; Li Zhou, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, School of Public Health and Management, Chongqing Medical University, Chongqing, China. Tel/Fax: +86-2368486780, E-mail:
| | - Li Zhou
- Department of Epidemiology, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, China
- Key Laboratory of Molecular Biology for Infectious Diseases, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- Corresponding Authors: Lihong Mu, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, School of Public Health and Management, Chongqing Medical University, Chongqing, China. Tel/Fax: +86-2368485008, E-mail: ; Li Zhou, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, School of Public Health and Management, Chongqing Medical University, Chongqing, China. Tel/Fax: +86-2368486780, E-mail:
| |
Collapse
|
|
35
|
Wasityastuti W, Yano Y, Ratnasari N, Triyono T, Triwikatmani C, Indrarti F, Heriyanto DS, Yamani LN, Liang Y, Utsumi T, Hayashi Y. Protective effects of HLA-DPA1/DPB1 variants against Hepatitis B virus infection in an Indonesian population. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2016; 41:177-184. [PMID: 27051043 DOI: 10.1016/j.meegid.2016.03.034] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Revised: 03/07/2016] [Accepted: 03/30/2016] [Indexed: 01/01/2023]
Abstract
Human leukocyte antigen (HLA) DPA1/DPB1 variants have been reported to influence Hepatitis B virus (HBV) infection. HLA-DPA1/DPB1 plays a pivotal role in antigen presentation to CD4(+) helper T cells and influences the outcome of HBV infection. To investigate the influence of HLA-DP variants on the outcome of HBV infection in an Indonesian population where it has the third-highest prevalence of HBV infection worldwide, we performed a case-control study of 686 participants, including patients with HBV-related advanced or nonadvanced liver disease, patients with spontaneously resolved HBV, and healthy controls. Single-nucleotide polymorphisms in HLA-DPA1 (rs3077) and HLA-DPB1 (rs3135021, rs9277535, and rs228388) were genotyped using real-time TaqMan® genotyping assays. Because rs2281388 deviated from Hardy-Weinberg equilibrium, it was excluded from subsequent analyses. The results of logistic regression analyses showed that the HLA-DPB1 rs9277535 variants were associated with a reduced risk of persistent HBV infection (odds ratio [OR] 0.70, 95% confidence interval [95% CI] 0.52-0.96, P=0.026, additive genetic model; OR 0.60, 95% CI 0.38-0.96, P=0.033, dominant genetic model). The HLA-DPA1 rs3077 variant was associated with a protective effect increasing the spontaneously resolved HBV infection (OR 0.64, 95% CI 0.41-0.98, P=0.039, dominant genetic model). By contrast, the HLA-DPB1 rs3135021 variant was not associated with the outcome of HBV infection, including susceptibility, spontaneously resolved, or disease progression. Combinations of haplotype markers were also associated with HBV susceptibility (CA for rs3077-rs9277535, OR 0.57, 95% CI 0.36-0.92, P=0.021; GA for rs3135021-rs9277535, OR 0.56, 95% CI 0.36-0.86, P=0.0087). In conclusion, these findings confirm that HLA-DPA1/DPB1 variants were associated with the outcomes of HBV infection in an Indonesian population.
Collapse
Affiliation(s)
- Widya Wasityastuti
- Division of Molecular Medicine & Medical Genetics, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Division of Infectious Disease Pathology, Department of Microbiology and Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Department of Physiology, Faculty of Medicine, Gadjah Mada University, Yogyakarta 55281, Indonesia
| | - Yoshihiko Yano
- Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
| | - Neneng Ratnasari
- Subdivision of Gastroenterohepatology, Department of Internal Medicine, Dr. Sardjito Hospital, Faculty of Medicine, Gadjah Mada University, Yogyakarta 55281, Indonesia
| | - Teguh Triyono
- Department of Clinical Pathology, Dr. Sardjito Hospital, Faculty of Medicine, Gadjah Mada University, Yogyakarta 55281, Indonesia
| | - Catharina Triwikatmani
- Subdivision of Gastroenterohepatology, Department of Internal Medicine, Dr. Sardjito Hospital, Faculty of Medicine, Gadjah Mada University, Yogyakarta 55281, Indonesia
| | - Fahmi Indrarti
- Subdivision of Gastroenterohepatology, Department of Internal Medicine, Dr. Sardjito Hospital, Faculty of Medicine, Gadjah Mada University, Yogyakarta 55281, Indonesia
| | - Didik Setyo Heriyanto
- Department of Anatomical Pathology, Dr. Sardjito Hospital, Faculty of Medicine, Gadjah Mada University, Yogyakarta 55281, Indonesia
| | - Laura Navika Yamani
- Division of Molecular Medicine & Medical Genetics, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Division of Infectious Disease Pathology, Department of Microbiology and Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Yujiao Liang
- Division of Molecular Medicine & Medical Genetics, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Division of Infectious Disease Pathology, Department of Microbiology and Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Takako Utsumi
- Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Indonesia-Japan Collaborative Research Centre for Emerging and Re-emerging Infectious Disease, Institute of Tropical Disease, Airlangga University, Surabaya 60115, Indonesia
| | - Yoshitake Hayashi
- Division of Molecular Medicine & Medical Genetics, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Division of Infectious Disease Pathology, Department of Microbiology and Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| |
Collapse
|
|
36
|
Xiang X, Guo Y, Yang L, Ge Q, Mijit S, Xu F. Association of human leukocyte antigen DP/DQ gene polymorphisms with chronic hepatitis B in Chinese Han and Uygur populations. INFECTION GENETICS AND EVOLUTION 2016; 43:407-11. [PMID: 27291710 DOI: 10.1016/j.meegid.2016.06.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 05/31/2016] [Accepted: 06/07/2016] [Indexed: 12/17/2022]
Abstract
Several genome-wide association studies (GWAS) have shown that human leukocyte antigen (HLA) DP/DQ gene polymorphisms are associated with susceptibility to chronic hepatitis B virus (HBV) infection. We clarified the roles of the HLA-DP/DQ gene in HBV infection in different nationalities. Three single nucleotide polymorphisms (SNPs) in HLA-DP (rs9277471, rs9277535 and rs9277542) and the SNP rs9272346 in HLA-DQ were studied. In total, 779 patients were recruited to this study, including 400 Chinese Han and 399 Uygurs. The rs9277535 variant genotypes were directly associated with HBV persistence compared to healthy controls in an additive model of the Chinese Han population (odds ratio [OR]=1.88, 95% confidence interval [CI]=1.03-3.41, P=0.040), and in a recessive model of the Chinese female population (OR=2.02, 95% CI=1.26-3.24, P=0.003). In addition, rs9277471 and rs9277542 variant genotypes significantly decreased the risk of HBV infection compared to healthy controls in an additive model of the Chinese Han population (OR=0.53, 95% CI=0.29-0.98, P=0.042; OR=0.53, 95% CI=0.29-0.97, P=0.039) and in a dominant model of the Chinese female population (OR=0.50, 95% CI=0.31-0.80, P=0.004; OR=0.49, 95% CI=0.31-0.79, P=0.003). The GG genotype of rs9277346 was associated with HBV infection in the Chinese Han population (additive model: OR=0.38, 95%CI=017-0.82, P=0.014; recessive model: OR=0.41, 95% CI=0.19-0.86, P=0.019) and in males (additive model: OR=0.31, 95% CI=0.14-0.65, P=0.002; dominant model: OR=0.65, 95% CI=0.43-0.97, P=0.034; recessive model: OR=0.36, 95% CI=0.18-0.73, P=0.005). In addition, allele G of rs9277346 was marginally related to a reduction in risk for HBV infection in the Uygur population. Our study suggests that HLA-DP/DQ polymorphisms can affect susceptibility and resistance to HBV infection in Chinese populations, and are possibly linked to race and sex.
Collapse
Affiliation(s)
- Xin Xiang
- Centre of Clinical Laboratory, the Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Yuxuan Guo
- Centre of Clinical Laboratory, the Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Li Yang
- Centre of Clinical Laboratory, the Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Qinghui Ge
- Centre of Clinical Laboratory, the Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China; College of Traditional Chinese Medicine, Xinjiang Medical University, Urumqi, China
| | - Sadatgul Mijit
- Centre of Clinical Laboratory, the Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China; College of Traditional Chinese Medicine, Xinjiang Medical University, Urumqi, China
| | - Feili Xu
- Centre of Clinical Laboratory, the Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China.
| |
Collapse
|
|
37
|
Wang L, Zou ZQ, Wang K. Clinical Relevance of HLA Gene Variants in HBV Infection. J Immunol Res 2016; 2016:9069375. [PMID: 27243039 PMCID: PMC4875979 DOI: 10.1155/2016/9069375] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 04/14/2016] [Indexed: 01/01/2023] Open
Abstract
Host gene variants may influence the natural history of hepatitis B virus (HBV) infection. The human leukocyte antigen (HLA) system, the major histocompatibility complex (MHC) in humans, is one of the most important host factors that are correlated with the clinical course of HBV infection. Genome-wide association studies (GWASs) have shown that single nucleotide polymorphisms (SNPs) near certain HLA gene loci are strongly associated with not only persistent HBV infection but also spontaneous HBV clearance and seroconversion, disease progression, and the development of liver cirrhosis and HBV-related hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB). These variations also influence the efficacy of interferon (IFN) and nucleot(s)ide analogue (NA) treatment and response to HBV vaccines. Meanwhile, discrepant conclusions were reached with different patient cohorts. It is therefore essential to identify the associations of specific HLA allele variants with disease progression and viral clearance in chronic HBV infection among different ethnic populations. A better understanding of HLA polymorphism relevance in HBV infection outcome would enable us to elucidate the roles of HLA SNPs in the pathogenesis and clearance of HBV in different areas and ethnic groups, to improve strategies for the prevention and treatment of chronic HBV infection.
Collapse
Affiliation(s)
- Li Wang
- Infectious Disease Hospital of Yantai, 62 Huanshan Road, Zhifu District, Yantai, Shandong 264001, China
| | - Zhi-Qiang Zou
- Infectious Disease Hospital of Yantai, 62 Huanshan Road, Zhifu District, Yantai, Shandong 264001, China
| | - Kai Wang
- Hepatology Department, Qilu Hospital of Shandong University, 44 Wenhua West Road, Lixia District, Jinan, Shandong 250012, China
| |
Collapse
|
|
38
|
Association of HLA-DP variants with the responsiveness to Hepatitis B virus vaccination in Korean Infants. Vaccine 2016; 34:2602-7. [PMID: 27083422 DOI: 10.1016/j.vaccine.2016.03.090] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Revised: 03/15/2016] [Accepted: 03/28/2016] [Indexed: 12/13/2022]
Abstract
Recently, HLA-DP single nucleotide polymorphisms (SNPs) have been reported to be related to responsiveness to hepatitis B virus (HBV) vaccination. The aim of this study was to investigate associations between HLA-DP SNPs and responsiveness to HBV vaccine in Korean infants. A total of 290 healthy Korean infants who were registered to Seoul Metropolitan Public Cord Blood Bank during the period of February 2007 to December 2011 were enrolled. Anti-HBs antibody level was analyzed after three doses of HBV vaccination. Genotyping of HLA-DPA1 SNPs (rs3077 and rs3830066) and HLA-DPB1 SNPs (rs7770370, rs7770501, rs3128961, and rs9277535) were performed by PCR-sequencing. HLA-A, -B, and -DRB1 genotyping was also performed by PCR-sequence-specific oligonucleotide probe kits. HLA-DPB1 SNPs (rs7770370, rs7770501, rs3128961, and rs9277535) were associated with HBV vaccine response. Allele frequencies of rs7770370 A, rs7770501 C, rs3128961 G, and rs9277535 A were significantly higher in responders than in non-responders (all p<0.01). Anti-HBs antibody levels were different according to genotypes of DPB1 rs7770370, rs7770501, rs3128961, and rs9277535 (all p<0.01). In multivariate analysis, HLA-DPB1 rs7770370 AA genotype was significantly associated with HBV vaccine response (relative risk, RR=2.5, p=0.033) and high-titer vaccine response (RR=2.7, p<0.001). In conclusion, HLA-DPB1 SNPs were significantly associated with responses to HBV vaccination in Korean infants.
Collapse
|
|
39
|
Association between microRNA-196A2 and microRNA-146A polymorphisms and progression to cirrhosis and hepatocellular carcinoma in patients with viral hepatitis B. Pharmacogenet Genomics 2016; 26:74-9. [DOI: 10.1097/fpc.0000000000000187] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
|
|
40
|
Chuang H, Huang LCS, Kapoor M, Liao YJ, Yang CL, Chang CC, Wu CY, Hwu JR, Huang TJ, Hsu MH. Design and synthesis of pyridine-pyrazole-sulfonate derivatives as potential anti-HBV agents. MEDCHEMCOMM 2016. [DOI: 10.1039/c6md00008h] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatitis B virus (HBV) is an infectious disease, which can cause acute and chronic infections.
Collapse
Affiliation(s)
- Hong Chuang
- Department of Chemistry
- National Tsing Hua University
- Hsinchu 30013
- Taiwan
- Nuclear Science & Technology Development Centre
| | - Lin-Chiang Sherlock Huang
- Department of Chemistry
- National Tsing Hua University
- Hsinchu 30013
- Taiwan
- Nuclear Science & Technology Development Centre
| | - Mohit Kapoor
- Department of Chemistry
- National Tsing Hua University
- Hsinchu 30013
- Taiwan
| | - Yi-Jen Liao
- School of Medical Laboratory Science and Biotechnology
- College of Medical Science and Technology
- Taipei Medical University
- Taiwan
| | - Cheng-Lin Yang
- Graduate Institute of Biomedical Sciences
- National Chung Hsing University
- Taichung 402
- Taiwan
| | - Chia-Ching Chang
- Department of Biology Science and Technology
- National Chiao Tung University
- Hsinchu
- Taiwan
| | - Chun-Yi Wu
- Department of Biomedical Imaging and Radiological Science
- China Medical University
- Taichung
- Taiwan
| | - Jih Ru Hwu
- Department of Chemistry
- National Tsing Hua University
- Hsinchu 30013
- Taiwan
| | | | - Ming-Hua Hsu
- Nuclear Science & Technology Development Centre
- National Tsing Hua University
- Hsinchu 30013
- Taiwan
| |
Collapse
|
|
41
|
Jiang DK, Ma XP, Wu X, Peng L, Yin J, Dan Y, Huang HX, Ding DL, Zhang LY, Shi Z, Zhang P, Yu H, Sun J, Lilly Zheng S, Deng G, Xu J, Liu Y, Guo J, Cao G, Yu L. Genetic variations in STAT4,C2,HLA-DRB1 and HLA-DQ associated with risk of hepatitis B virus-related liver cirrhosis. Sci Rep 2015; 5:16278. [PMID: 26538132 PMCID: PMC4633722 DOI: 10.1038/srep16278] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 10/05/2015] [Indexed: 12/16/2022] Open
Abstract
Recent genome-wide associated studies (GWASs) have revealed several common loci associated with the risk of hepatitis B virus (HBV)- or hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). We selected 15 single nucleotide polymorphisms (SNPs) identified through GWASs on HBV- or HCV-related HCC, and genotyped them in two independent Chinese cohorts of chronic HBV carriers, including 712 LC cases and 2601 controls. The association of each SNP with the risk of HBV-related LC was assessed by meta-analysis of the two cohorts. Of the 12 SNPs reported in HBV-related HCC GWASs, five SNPs (rs7574865 in STAT4, rs9267673 near C2, rs2647073 and rs3997872 near HLA-DRB1 and rs9275319 near HLA-DQ), were found to be significantly associated with the risk of HBV-related LC (rs7574865: P = 1.79 × 10(-2), OR = 1.17, 95% CI = 1.03-1.34; rs9267673: P = 4.91 × 10(-4), OR = 1.37, 95% CI = 1.15-1.63; rs2647073: P = 3.53 × 10(-5), OR = 1.63, 95% CI = 1.29-2.06; rs3997872: P = 4.22 × 10(-4), OR = 1.86, 95% CI = 1.32-2.62; rs9275319: P = 1.30 × 10(-2), OR = 1.32, 95% CI = 1.06-1.64). However, among the three SNPs associated with the risk of HCV-related HCC in previous GWASs, none of them showed significant association with the risk of HBV-related LC. Our results suggested that genetic variants associated with HBV-related hepatocarcinogenesis may already play an important role in the progression from CHB to LC.
Collapse
Affiliation(s)
- De-Ke Jiang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Center for Genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, China
- Center for Genetic Translational Medicine and Prevention, Fudan University, Shanghai, China
- Center for Cancer Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA
- Program for Personalized Cancer Care, NorthShore University HealthSystem, the University of Chicago, IL, USA
| | - Xiao-Pin Ma
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Xiaopan Wu
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Lijun Peng
- Division of Digestive Diseases, Zhongshan Hospital, Department of Internal Medicine, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jianhua Yin
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Yunjie Dan
- Department of Infectious Diseases, Southwest Hospital, Institute of Immunology, Third Military Medical University, and Chongqing Key Laboratory of Infectious Diseases, Chongqing, China
| | - Hui-Xing Huang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Dong-Lin Ding
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Lu-Yao Zhang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Zhuqing Shi
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Center for Genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, China
- Center for Genetic Translational Medicine and Prevention, Fudan University, Shanghai, China
| | - Pengyin Zhang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Center for Genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, China
- Center for Genetic Translational Medicine and Prevention, Fudan University, Shanghai, China
| | - Hongjie Yu
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Center for Genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, China
- Center for Genetic Translational Medicine and Prevention, Fudan University, Shanghai, China
| | - Jielin Sun
- Center for Cancer Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - S. Lilly Zheng
- Center for Cancer Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA
- Program for Personalized Cancer Care, NorthShore University HealthSystem, the University of Chicago, IL, USA
| | - Guohong Deng
- Department of Infectious Diseases, Southwest Hospital, Institute of Immunology, Third Military Medical University, and Chongqing Key Laboratory of Infectious Diseases, Chongqing, China
| | - Jianfeng Xu
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Center for Genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, China
- Center for Genetic Translational Medicine and Prevention, Fudan University, Shanghai, China
- Center for Cancer Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA
- Program for Personalized Cancer Care, NorthShore University HealthSystem, the University of Chicago, IL, USA
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Ying Liu
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Jinsheng Guo
- Division of Digestive Diseases, Zhongshan Hospital, Department of Internal Medicine, Shanghai Medical College, Fudan University, Shanghai, China
| | - Guangwen Cao
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Long Yu
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
- Institute of Biomedical Science, Fudan University, Shanghai, China
| |
Collapse
|
|
42
|
Yano Y, Utsumi T, Lusida MI, Hayashi Y. Hepatitis B virus infection in Indonesia. World J Gastroenterol 2015; 21:10714-20. [PMID: 26478663 PMCID: PMC4600573 DOI: 10.3748/wjg.v21.i38.10714] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 07/14/2015] [Accepted: 09/15/2015] [Indexed: 02/06/2023] Open
Abstract
Approximately 240 million people are chronically infected with hepatitis B virus (HBV), 75% of whom reside in Asia. Approximately 600000 of infected patients die each year due to HBV-related diseases or hepatocellular carcinoma (HCC). The endemicity of hepatitis surface antigen in Indonesia is intermediate to high with a geographical difference. The risk of HBV infection is high in hemodialysis (HD) patients, men having sex with men, and health care workers. Occult HBV infection has been detected in various groups such as blood donors, HD patients, and HIV-infected individuals and children. The most common HBV subgenotype in Indonesia is B3 followed by C1. Various novel subgenotypes of HBV have been identified throughout Indonesia, with the novel HBV subgenotypes C6-C16 and D6 being successfully isolated. Although a number of HBV subgenotypes have been discovered in Indonesia, genotype-related pathogenicity has not yet been elucidated in detail. Therefore, genotype-related differences in the prognosis of liver disease and their effects on treatments need to be determined. A previous study conducted in Indonesia revealed that hepatic steatosis was associated with disease progression. Pre-S2 mutations and mutations at C1638T and T1753V in HBV/B3 have been associated with advanced liver diseases including HCC. However, drug resistance to lamivudine, which is prominent in Indonesia, remains obscure. Although the number of studies on HBV in Indonesia has been increasing, adequate databases on HBV infection are limited. We herein provided an overview of the epidemiology and clinical characteristics of HBV infection in Indonesia.
Collapse
|
|
43
|
Quantitative assessment of common genetic variations in HLA-DP with hepatitis B virus infection, clearance and hepatocellular carcinoma development. Sci Rep 2015; 5:14933. [PMID: 26462556 PMCID: PMC4604517 DOI: 10.1038/srep14933] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 09/11/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is the predominant risk factor for chronic hepatitis B (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Recently, genome-wide association studies have identified human leukocyte antigen (HLA)-DP polymorphisms (rs3077 and rs9277535) as a new chronic HBV infection susceptibility locus. Since then, the relationship between HLA-DP polymorphisms and various outcomes of HBV infection has been reported. However, the results have been inconclusive. To derive a more precise estimation of the relationship between HLA-DP polymorphisms and various outcomes of HBV infection, a meta-analysis of 62,050 subjects from 29 case-control studies was performed. We found that rs3077 and rs9277535 in HLA-DP significantly decreased HBV infection risks and increased HBV clearance possibility in a dose-dependent manner. In the subgroup analysis by ethnicity, study design and sample size, significant associations were found for these polymorphisms in almost all comparisons. Meanwhile, haplotype analyses of the two polymorphisms revealed a significant association between the combination of these alleles and HBV infection outcomes. However, no significant results were observed in HCC development. Our results further confirm that genetic variants in the HLA-DP locus are strongly associated with reduced HBV infection and increased the likelihood of spontaneous viral clearance.
Collapse
|
|
44
|
Nishida N, Ohashi J, Sugiyama M, Tsuchiura T, Yamamoto K, Hino K, Honda M, Kaneko S, Yatsuhashi H, Koike K, Yokosuka O, Tanaka E, Taketomi A, Kurosaki M, Izumi N, Sakamoto N, Eguchi Y, Sasazuki T, Tokunaga K, Mizokami M. Effects of HLA-DPB1 genotypes on chronic hepatitis B infection in Japanese individuals. ACTA ACUST UNITED AC 2015; 86:406-12. [PMID: 26449183 DOI: 10.1111/tan.12684] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Revised: 09/04/2015] [Accepted: 09/15/2015] [Indexed: 01/26/2023]
Abstract
Significant associations of HLA-DP alleles with chronic hepatitis B (CHB) infection are evident in Asian and Arabian populations, including Japanese, Han Chinese, Korean, and Saudi Arabian populations. Here, significant associations between CHB infection and five DPB1 alleles (two susceptibility alleles, DPB1(*) 05:01 and (*) 09:01, and three protective alleles, DPB1(*) 02:01, (*) 04:01, and (*) 04:02) were confirmed in a population comprising of 2582 Japanese individuals. Furthermore, odds ratios for CHB were higher for those with both DPB1 susceptibility alleles than for those with only one susceptibility allele; therefore, effects of susceptibility alleles were additive for risk of CHB infection. Similarly, protective alleles showed an additive effect on protection from CHB infection. Moreover, heterozygotes of any protective allele showed stronger association with CHB than did homozygotes, suggesting that heterozygotes may bind a greater variety of hepatitis B-derived peptides, and thus present these peptides more efficiently to T-cell receptors than homozygotes. Notably, compound heterozygote of the protective allele (any one of DPB1*02:01, *04:01, and *04:02) and the susceptible allele DPB1*05:01 was significantly associated with protection against CHB infection, which indicates that one protective HLA-DPB1 molecule can provide dominant protection. Identification of the HLA-DPB1 genotypes associated with susceptibility to and protection from CHB infection is essential for future analysis of the mechanisms responsible for immune recognition of hepatitis B virus antigens by HLA-DPB1 molecules.
Collapse
Affiliation(s)
- N Nishida
- Department of Hepatic Disease, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan.,Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - J Ohashi
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan
| | - M Sugiyama
- Department of Hepatic Disease, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
| | - T Tsuchiura
- Department of Hepatic Disease, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
| | - K Yamamoto
- Department of Medical Chemistry, Kurume University School of Medicine, Kurume, Japan
| | - K Hino
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan
| | - M Honda
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - S Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - H Yatsuhashi
- Clinical Research Center, National Nagasaki Medical Center, Nagasaki, Japan
| | - K Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - O Yokosuka
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - E Tanaka
- Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - A Taketomi
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - M Kurosaki
- Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - N Izumi
- Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - N Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Y Eguchi
- Division of Hepatology, Saga Medical School, Saga, Japan
| | - T Sasazuki
- Institute for Advanced Study, Kyushu University, Fukuoka, Japan
| | - K Tokunaga
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - M Mizokami
- Department of Hepatic Disease, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
| |
Collapse
|
|
45
|
IL6 gene allele-specific C/EBPα-binding activity affects the development of HBV infection through modulation of Th17/Treg balance. Genes Immun 2015; 16:528-35. [PMID: 26447433 DOI: 10.1038/gene.2015.40] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Revised: 08/13/2015] [Accepted: 08/20/2015] [Indexed: 12/15/2022]
Abstract
Interleukin-6 (IL-6) has an important role in the pathogenesis of chronic viral hepatitis and related liver diseases. Although host genetics associated with the response to anti-viral treatment have been reported, little is known about the relationship between IL6 genetic polymorphisms and the outcome of hepatitis B virus (HBV) infection. In this study, we determined the genotype distribution of rs1800796 polymorphism in healthy controls and cases including chronic HBV (CHB), hepatitis C virus and HIV infection. The rs1800796 was found to be associated with clinical outcome of CHB in experimental and validation cohort. The rs1800796C allele has twofold higher promoter activity than G allele. Consistently, CD14(+) monocytes from subjects carrying the rs1800796C allele produced more IL-6 in response to in vitro HBV core antigen stimulation than those carrying G allele. Moreover, CHB patients carrying rs1800796C allele have significantly higher T-helper 17 (Th17) and regulatory T cell (Treg) ratio. Finally, a transcription factor C/EBPα binds in higher affinity to rs1800796C allele than to G allele. These results suggest that genetic predisposition to higher IL-6 production is associated with increased risk to HBV infection and hepatic inflammation, which might be due to C/EBPα-mediated regulatory effect on Th17 and Treg responses. Appropriate manipulation of IL-6 expression might be used to prevent and treat HBV infection.
Collapse
|
|
46
|
Yang YC, Chang TY, Chen TC, Lin WS, Chang SC, Lee YJ. Genetic susceptibility to cervical squamous cell carcinoma is associated with HLA-DPB1 polymorphisms in Taiwanese women. Cancer Immunol Immunother 2015; 64:1151-7. [PMID: 26031576 PMCID: PMC11028884 DOI: 10.1007/s00262-015-1721-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Accepted: 05/21/2015] [Indexed: 11/29/2022]
Abstract
Cervical cancer is a multifactorial disease, and increasing evidence suggests that host immunogenetic background may contribute to its pathogenesis. Genetic variations in human leukocyte antigen (HLA) genes may alter the efficiency of immune response to human papillomavirus (HPV) antigens and have been implicated in the risk of cervical cancer. We investigated whether polymorphisms in the HLA-DPB1 gene were associated with cervical cancer risk in a Taiwanese population. HLA-DPB1 alleles and +550 G/A polymorphism were genotyped in a case-control study of 473 women with cervical squamous cell carcinoma (CSCC) and 676 healthy controls. The presence and genotypes of HPV in CSCC were determined. We found that the DPB1*05:01 and +550 A alleles were associated with decreased and increased risk of CSCC, respectively [odds ratio (OR) = 0.72, Pc = 0.001; OR = 1.25, Pc = 0.03]. In subgroup analysis based on HPV type 16 positivity, significant associations were shown in the DPB1*05:01 and *13:01 alleles (OR = 0.65, Pc = 0.0007; OR = 1.83, Pc = 0.004). Furthermore, the DPB1*05:01-G and *13:01-G haplotypes conferred decreased and increased risk of both CSCC and HPV-16 positive CSCC women, respectively (OR = 0.72, Pc = 0.0009; OR = 0.63, Pc = 0.0004 for DPB1*05:01-G; OR = 1.55, Pc = 0.03; OR = 1.84, Pc = 0.004 for DPB1*13:01-G). A risk haplotype DPB1*02:01-A was also observed in the HPV-16 positive CSCC women (OR = 1.51, Pc = 0.05). These findings suggest that HLA-DPB1 gene is involved in the CSCC development.
Collapse
Affiliation(s)
- Yuh-Cheng Yang
- Department of Gynecology and Obstetrics, Mackay Memorial Hospital, Taipei City, Taiwan
- Department of Gynecology and Obstetrics, Taipei Medical University, Taipei City, Taiwan
| | - Tzu-Yang Chang
- Department of Medical Research, Mackay Memorial Hospital, New Taipei City, Taiwan
| | - Tze-Chien Chen
- Department of Gynecology and Obstetrics, Mackay Memorial Hospital, Taipei City, Taiwan
| | - Wen-Shan Lin
- Department of Medical Research, Mackay Memorial Hospital, New Taipei City, Taiwan
| | - Shih-Chuan Chang
- Department of Medical Research, Mackay Memorial Hospital, New Taipei City, Taiwan
| | - Yann-Jinn Lee
- Department of Pediatrics, Mackay Memorial Hospital, Taipei City, Taiwan
- Department of Medical Research, Mackay Memorial Hospital, New Taipei City, Taiwan
- Department of Pediatrics, Taipei Medical University, Taipei City, Taiwan
- Institute of Biomedical Sciences and Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
| |
Collapse
|
|
47
|
Matsuura K, Isogawa M, Tanaka Y. Host genetic variants influencing the clinical course of hepatitis B virus infection. J Med Virol 2015; 88:371-9. [PMID: 26255971 DOI: 10.1002/jmv.24350] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/05/2015] [Indexed: 12/22/2022]
Abstract
The clinical course of hepatitis B virus (HBV) infection greatly differs in individuals. Various viral, host, and environmental factors influence the natural history of HBV infection. Recent genome-wide association studies identified several host genetic factors influencing the clinical course of HBV infection. Genetic variations in HLA class II loci were significantly associated with susceptibility to persistent HBV infection. Other polymorphisms in or near the genes EHMT2, TCF19, and HLA-C, located near HLA class II loci, and UBE2L3 were also associated with persistent HBV infection. Meanwhile, polymorphisms in KIF1B, GRIK1, and STAT4 were associated with HBV-related hepatocellular carcinoma (HCC). Interestingly, HLA class II genetic variations were strongly associated with not only persistent HBV infection, but also disease progression and HBV-related HCC in chronic hepatitis B. Understanding the various genetic factors associated with the clinical course of HBV infection is essential for personalized treatment and surveillance of disease progression and HCC.
Collapse
Affiliation(s)
- Kentaro Matsuura
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.,Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.,Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Masanori Isogawa
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| |
Collapse
|
|
48
|
He D, Tao S, Guo S, Li M, Wu J, Huang H, Guo X, Yan G, Zhu P, Wang Y. Interaction of TLR-IFN and HLA polymorphisms on susceptibility of chronic HBV infection in Southwest Han Chinese. Liver Int 2015; 35:1941-1949. [PMID: 25469587 PMCID: PMC6680266 DOI: 10.1111/liv.12756] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Accepted: 11/27/2014] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS The toll-like receptor-interferon (TLR-IFN) signalling pathway plays a crucial role in HBV infection. Human leucocyte antigen (HLA) polymorphisms are associated with chronic HBV infection by genome wide association study (GWAS). We aimed to explore interaction between TLR-IFN and HLA gene polymorphisms in susceptibility of chronic HBV infection. METHODS In the Chinese Southwest Han population, 1191 chronic HBV infection patients and 273 HBV clearance were selected. A total of 39 single nucleotide polymorphism loci in 23 genes of the TLR-IFN pathway and four HLA polymorphism loci associated with chronic HBV infection identified by GWAS were selected for genotyping. SNPStats, QVALUE, and multifactor dimensionality reduction were used for statistical analysis. RESULTS A significant association was seen in several of the TLR-IFN pathway genes, TLR9 rs352140 (OR = 0.70, P = 0.0088), IL1B rs16944 (OR = 0.67, P = 0.016), IL12B rs3212227 (OR = 1.38, P = 0.021), IFNGR1 rs3799488 (OR = 1.48, P = 0.0048), IFNGR2 rs1059293 (OR = 0.27, P = 0.011), MX1 rs467960 (OR = 0.68, P = 0.022), as well as four loci in HLA, rs3077 (OR = 0.55, P < 0.0001), rs2856718 (OR = 0.60, P = 4e-04), rs9277535 (OR = 0.54, P < 0.0001) and rs7453920 (OR = 0.43, P < 0.0001). A synergistic relationship was seen between rs9277535 and rs16944 (0.13%), rs1143623 and rs6613 (0.10%). The combination of rs9277535 in HLA and rs16944 in IL1B was the best model to predict chronic HBV infection (testing accuracy = 0.6040, P = 0.0010, cross-validation consistency = 10/10). CONCLUSIONS TLR-IFN pathway gene polymorphisms are associated with chronic HBV infection. Interactions with polymorphisms in these genes may be one mechanism by which HLA polymorphisms influence susceptibility to chronic HBV infection, as specific single nucleotide polymorphism combinations are highly predictive of chronic HBV infection.
Collapse
Affiliation(s)
- Dengming He
- Institute of Infectious DiseaseSouthwest HospitalThird Military Medical UniversityChongqingChina
- Liver Disease Diagnoses and Treatment Center of Chinese PLAThe 88th Hospital of Chinese PLATai'anShandong ProvinceChina
- The Chongqing Key Laboratory for Research of Infectious DiseasesChongqingChina
| | - Shiqi Tao
- Institute of Infectious DiseaseSouthwest HospitalThird Military Medical UniversityChongqingChina
- The Chongqing Key Laboratory for Research of Infectious DiseasesChongqingChina
| | - Shimin Guo
- Institute of Infectious DiseaseSouthwest HospitalThird Military Medical UniversityChongqingChina
- The Chongqing Key Laboratory for Research of Infectious DiseasesChongqingChina
| | - Maoshi Li
- Institute of Infectious DiseaseSouthwest HospitalThird Military Medical UniversityChongqingChina
- The Chongqing Key Laboratory for Research of Infectious DiseasesChongqingChina
| | - Junqiu Wu
- Institute of Infectious DiseaseSouthwest HospitalThird Military Medical UniversityChongqingChina
- The Chongqing Key Laboratory for Research of Infectious DiseasesChongqingChina
| | - Hongfei Huang
- Institute of Infectious DiseaseSouthwest HospitalThird Military Medical UniversityChongqingChina
- The Chongqing Key Laboratory for Research of Infectious DiseasesChongqingChina
| | - Xinwu Guo
- Institute of Infectious DiseaseSouthwest HospitalThird Military Medical UniversityChongqingChina
- The Chongqing Key Laboratory for Research of Infectious DiseasesChongqingChina
- Sansure Biotech Inc.ChangshaHunan ProvinceChina
| | - Guohua Yan
- Institute of Infectious DiseaseSouthwest HospitalThird Military Medical UniversityChongqingChina
- The Chongqing Key Laboratory for Research of Infectious DiseasesChongqingChina
| | - Peng Zhu
- Institute of Infectious DiseaseSouthwest HospitalThird Military Medical UniversityChongqingChina
- The Chongqing Key Laboratory for Research of Infectious DiseasesChongqingChina
| | - Yuming Wang
- Institute of Infectious DiseaseSouthwest HospitalThird Military Medical UniversityChongqingChina
- The Chongqing Key Laboratory for Research of Infectious DiseasesChongqingChina
| |
Collapse
|
|
49
|
Human Leukocyte Antigen Class II Alleles Are Associated with Hepatitis C Virus Natural Susceptibility in the Chinese Population. Int J Mol Sci 2015. [PMID: 26213920 PMCID: PMC4581170 DOI: 10.3390/ijms160816792] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Human leukocyte antigen (HLA) class II molecule influences host antigen presentation and anti-viral immune response. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) within HLA class II gene were associated with different clinical outcomes of hepatitis C virus (HCV) infection. Three HLA class II SNPs (rs3077, rs2395309 and rs2856718) were genotyped by TaqMan assay among Chinese population, including 350 persistent HCV infection patients, 194 spontaneous viral clearance subjects and 973 HCV-uninfected control subjects. After logistic regression analysis, the results indicated that the rs2856718 TC genotype was significantly associated with the protective effect of the HCV natural susceptibility (adjusted OR: 0.712, 95% CI: 0.554–0.914) when compared with reference TT genotype, and this remained significant after false discovery rate (FDR) correction (p = 0.024). Moreover, the protective effect of rs2856718 was observed in dominant genetic models (adjusted OR: 0.726, 95% CI: 0.574–0.920), and this remained significant after FDR correction (p = 0.024). In stratified analysis, a significant decreased risk was found in rs2856718C allele in the male subgroup (adjusted OR: 0.778, 95% CI: 0.627–0.966) and hemodialysis subgroup (adjusted OR: 0.713, 95% CI: 0.552–0.921). Our results indicated that the genetic variations of rs2856718 within the HLA-DQ gene are associated with the natural susceptibility to HCV infection among the Chinese population.
Collapse
|
|
50
|
Tao J, Su K, Yu C, Liu X, Wu W, Xu W, Jiang B, Luo R, Yao J, Zhou J, Zhan Y, Ye C, Yuan W, Jiang X, Cui W, Li MD, Li L. Fine mapping analysis of HLA-DP/DQ gene clusters on chromosome 6 reveals multiple susceptibility loci for HBV infection. Amino Acids 2015. [PMID: 26197724 DOI: 10.1007/s00726-015-2054-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Recent genome-wide association studies have revealed the HLA region on chromosome 6p21 as a susceptibility locus for hepatitis B virus (HBV) infection, a finding subsequently replicated in independent samples. However, only limited single nucleotide polymorphisms (SNPs) were analyzed in most of these studies, and it remains to be determined which SNPs contribute to the detected association. After genotyping 140 SNPs within this genomic region in a total of 1657 HBV-positive patients and 1456 HBV-negative controls, we conducted a series of genetic epidemiological and bioinformatics analysis, including individual SNP-based association analysis, haplotype-based association analysis, and conditional analysis. We identified 76 SNPs and 5 LD blocks in HLA-DP/DQ clusters that are significantly associated with HBV infection, with the smallest P value being 3.88 × 10(-18) for rs9277535 in HLA-DPB1. With conditional analysis, we further revealed that the genes contributing to the effects of variants in HLA-DP/DQ on infection are independent of each other, and the LD block 5 in the 3'-UTR region of HLA-DPB1 had a predominant effect in the association of HLA-DP with HBV infection. We also found that the SNPs in the 3'-UTR region of HLA-DPB1 were significant between the subgroups of inactive HBV carrier, chronic hepatitis B, or hepatic cirrhosis from the case group and the spontaneous HBV-clearance subgroup from the control group. Finally, we did further association analysis of SNPs in this region with different subgroups from the case group, which revealed no association of these SNPs with the progression of HBV-related diseases. In sum, we showed, for the first time, that the HLA-DP/DQ clusters contribute independently to HBV infection, and the 3'-UTR region of HLA-DPB1 represents an important functional region involved in HBV infection.
Collapse
Affiliation(s)
- Jingjing Tao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Kunkai Su
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Chengbo Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Xiaoli Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Wei Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Wei Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Bingxun Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Rui Luo
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Jian Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Jiawei Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Yan Zhan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Chao Ye
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Wenji Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Xianzhong Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Wenyan Cui
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Ming D Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China. .,Department of Psychiatry and Neurobehavioral Science, University of Virginia, 450 Ray C Hunt Drive, Charlottesville, VA, 22903, USA.
| | - Lianjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China.
| |
Collapse
|