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Tălăngescu A, Tizu M, Calenic B, Mihăilescu DF, Constantinescu AE, Constantinescu I. HLA Genetic Diversity and Chronic Hepatitis B Virus Infection: Effect of Heterozygosity Advantage. Med Sci (Basel) 2024; 12:44. [PMID: 39311157 PMCID: PMC11417839 DOI: 10.3390/medsci12030044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 08/20/2024] [Accepted: 08/27/2024] [Indexed: 09/26/2024] Open
Abstract
This research aims to determine whether HLA heterozygosity confers a protective effect against hepatitis B virus infection by analyzing the relationship between HLA diversity and the risk of hepatitis B virus (HBV) infection. A total of 327 hepatitis B patients were selected and categorized based on their clinical status: 284 patients with chronic HBV infection and 43 patients with HBV-related liver cirrhosis (LC). The control group included 304 healthy individuals. HLA genotyping for 11 loci, including HLA class I and class II, was conducted using next-generation sequencing. The results of this study indicate a statistically significant negative correlation between HLA class II heterozygosity and the risk of HBV infection. Specifically, heterozygosity in HLA-DQB1 (OR = 0.49, 95% CI = 0.31-0.76, p = 0.01277) and HLA-DRB1 (OR = 0.42, 95% CI = 0.24-0.77, p = 0.01855) were significantly associated with protection. Subgroup analysis was conducted to explore the effect of HLA diversity among pathological subtypes (chronic hepatitis B and control group, liver cirrhosis and control group). For liver cirrhosis, compared with the control group, a decreased risk of LC was possibly associated with the heterozygosity of HLA class I locus B (OR = 0.24, 95% CI = 0.09-0.65, p = 0.0591), but this hypothesis was not confirmed by other studies. The diversity of HLA, measured by HLA heterozygosity, was associated with a protective effect against HBV infection.
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Affiliation(s)
- Adriana Tălăngescu
- Immunology and Transplant Immunology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (A.T.); (B.C.); (A.E.C.); (I.C.)
- Centre of Immunogenetics and Virology, Fundeni Clinical Institute, 258 Fundeni Avenue, 022328 Bucharest, Romania
| | - Maria Tizu
- Immunology and Transplant Immunology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (A.T.); (B.C.); (A.E.C.); (I.C.)
- Centre of Immunogenetics and Virology, Fundeni Clinical Institute, 258 Fundeni Avenue, 022328 Bucharest, Romania
| | - Bogdan Calenic
- Immunology and Transplant Immunology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (A.T.); (B.C.); (A.E.C.); (I.C.)
| | - Dan Florin Mihăilescu
- Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Splaiul Independentei Street, No. 91–95, 050095 Bucharest, Romania;
| | - Alexandra Elena Constantinescu
- Immunology and Transplant Immunology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (A.T.); (B.C.); (A.E.C.); (I.C.)
- “Emil Palade” Centre of Excellence for Young People in Scientific Research (EP-CEYR), 3 Ilfov Street, Sector 5, 050045 Bucharest, Romania
| | - Ileana Constantinescu
- Immunology and Transplant Immunology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (A.T.); (B.C.); (A.E.C.); (I.C.)
- Centre of Immunogenetics and Virology, Fundeni Clinical Institute, 258 Fundeni Avenue, 022328 Bucharest, Romania
- “Emil Palade” Centre of Excellence for Young People in Scientific Research (EP-CEYR), 3 Ilfov Street, Sector 5, 050045 Bucharest, Romania
- Academy of Romanian Scientists (AOSR), 3 Ilfov Street, Sector 5, 050045 Bucharest, Romania
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Liu J, Yu Y, Zhao H, Guo L, Yang W, Yan Y, Lv J. Latest insights into the epidemiology, characteristics, and therapeutic strategies of chronic hepatitis B patients in indeterminate phase. Eur J Med Res 2024; 29:343. [PMID: 38902822 PMCID: PMC11191257 DOI: 10.1186/s40001-024-01942-0] [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: 05/18/2023] [Accepted: 06/17/2024] [Indexed: 06/22/2024] Open
Abstract
As a hepatotropic virus, hepatitis B virus (HBV) can establish a persistent chronic infection in the liver, termed, chronic hepatitis B (CHB), which causes a series of liver-related complications, including fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HCC with HBV infection has a significantly increased morbidity and mortality, whereas it could be preventable. The current goal of antiviral therapy for HBV infection is to decrease CHB-related morbidity and mortality, and achieve sustained suppression of virus replication, which is known as a functional or immunological cure. The natural history of chronic HBV infection includes four immune phases: the immune-tolerant phase, immune-active phase, inactive phase, and reactivation phase. However, many CHB patients do not fit into any of these defined phases and are regarded as indeterminate. A large proportion of indeterminate patients are only treated with dynamic monitoring rather than recommended antiviral therapy, mainly due to the lack of definite guidelines. However, many of these patients may gradually have significant liver histopathological changes during disease progression. Recent studies have focused on the prevalence, progression, and carcinogenicity of indeterminate CHB, and more attention has been given to the prevention, detection, and treatment for these patients. Herein, we discuss the latest understanding of the epidemiology, clinical characteristics, and therapeutic strategies of indeterminate CHB, to provide avenues for the management of these patients.
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Affiliation(s)
- Junye Liu
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Yan Yu
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Heping Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Lei Guo
- Department of Spinal Surgery, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Wenjuan Yang
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Yuzhu Yan
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Jing Lv
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China.
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Tălăngescu A, Calenic B, Mihăilescu DF, Tizu M, Marunțelu I, Constantinescu AE, Constantinescu I. Molecular Analysis of HLA Genes in Romanian Patients with Chronic Hepatitis B Virus Infection. Curr Issues Mol Biol 2024; 46:1064-1077. [PMID: 38392185 PMCID: PMC10887826 DOI: 10.3390/cimb46020067] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 01/16/2024] [Accepted: 01/22/2024] [Indexed: 02/24/2024] Open
Abstract
Hepatitis B, a persistent inflammatory liver condition, stands as a significant global health issue. In Romania, the prevalence of chronic hepatitis B virus (CHB) infection ranks among the highest in the European Union. The HLA genotype significantly impacts hepatitis B virus infection progression, indicating that certain HLA variants can affect the infection's outcome. The primary goal of the present work is to identify HLA alleles and specific amino acid residues linked to hepatitis B within the Romanian population. The study enrolled 247 patients with chronic hepatitis B; HLA typing was performed using next-generation sequencing. This study's main findings include the identification of certain HLA alleles, such as DQB1*06:03:01, DRB1*13:01:01, DQB1*06:02:01, DQA1*01:03:01, DRB5*01:01:01, and DRB1*15:01:01, which exhibit a significant protective effect against HBV. Additionally, the amino acid residue alanine at DQB1_38 is associated with a protective role, while valine presence may signal an increased risk of hepatitis B. The present findings are important in addressing the urgent need for improved methods of diagnosing and managing CHB, particularly when considering the disease's presence in diverse population groups and geographical regions.
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Affiliation(s)
- Adriana Tălăngescu
- Immunology and Transplant Immunology, Carol Davila University of Medicine and Pharmacy, 258 Fundeni Avenue, 022328 Bucharest, Romania
- Centre of Immunogenetics and Virology, Fundeni Clinical Institute, 258 Fundeni Avenue, 022328 Bucharest, Romania
| | - Bogdan Calenic
- Immunology and Transplant Immunology, Carol Davila University of Medicine and Pharmacy, 258 Fundeni Avenue, 022328 Bucharest, Romania
| | - Dan Florin Mihăilescu
- Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Splaiul Independenței Street, No. 91-95, 050095 Bucharest, Romania
| | - Maria Tizu
- Immunology and Transplant Immunology, Carol Davila University of Medicine and Pharmacy, 258 Fundeni Avenue, 022328 Bucharest, Romania
- Centre of Immunogenetics and Virology, Fundeni Clinical Institute, 258 Fundeni Avenue, 022328 Bucharest, Romania
| | - Ion Marunțelu
- Immunology and Transplant Immunology, Carol Davila University of Medicine and Pharmacy, 258 Fundeni Avenue, 022328 Bucharest, Romania
- Centre of Immunogenetics and Virology, Fundeni Clinical Institute, 258 Fundeni Avenue, 022328 Bucharest, Romania
| | - Alexandra E Constantinescu
- Immunology and Transplant Immunology, Carol Davila University of Medicine and Pharmacy, 258 Fundeni Avenue, 022328 Bucharest, Romania
| | - Ileana Constantinescu
- Immunology and Transplant Immunology, Carol Davila University of Medicine and Pharmacy, 258 Fundeni Avenue, 022328 Bucharest, Romania
- Centre of Immunogenetics and Virology, Fundeni Clinical Institute, 258 Fundeni Avenue, 022328 Bucharest, Romania
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Setoyama H, Nishida N, Nagashima S, Ko K, Yamazoe T, Tanaka Y, Mizokami M, Tanaka J, Kanto T. Dried blood spot-based host genome analysis technique targeting pathological associations with hepatitis B: Development and clinical application in the Cambodian population. Hepatol Res 2023; 53:1147-1155. [PMID: 37522242 DOI: 10.1111/hepr.13949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 07/21/2023] [Accepted: 07/28/2023] [Indexed: 08/01/2023]
Abstract
AIM Reports of patients with hepatitis B have highlighted associations between polymorphisms in the human leukocyte antigen (HLA)-DPB1, CXCL13, and CXCR5 genes and disease pathology. Owing to its potential to contribute to the development of new diagnostic and therapeutic methods, we aimed to establish a reliable host genome analysis technique that can be used in countries with inadequate infrastructure. METHOD We compared multiple commercially available kits for dried blood spot (DBS)-based sample collection to develop a basic DBS-based host genome analysis technique. We then collected blood samples from Cambodian patients with hepatitis B and performed single-nucleotide polymorphism genotyping and HLA allele typing by the DBS system. RESULT We were able to perform single-nucleotide polymorphism genotyping and HLA allele typing with host DNA samples obtained using a combination of a HemaSpot™ filter paper-based device and a SMITEST® EX-R&D DNA extraction kit. The accuracy of genotyping using samples obtained by this method was not inferior to one using samples obtained by venipuncture. In the Cambodian population, significant associations of HLA-DPB1*04:01 with protection against chronic hepatitis B virus (HBV) infection, and HLA-DPB1*05:01 and HLA-DPB1*13:01 with susceptibility to chronic HBV infection were identified. CONCLUSION Based on the DBS system, we clarified the associations of HLA-DPB1 alleles with chronic HBV infection in the Cambodian population for the first time. Because the DBS is a low-cost, durable, transportable, and easy-to-handle modality, genetic analysis based on the DBS system is a feasible strategy for obtaining a deeper understanding of HBV epidemiology, especially in middle- or low-income countries.
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Affiliation(s)
- Hiroko Setoyama
- Hepatitis Information Center, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Nao Nishida
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Shintaro Nagashima
- Department of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Ko Ko
- Department of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Taiji Yamazoe
- Hepatitis Information Center, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Masashi Mizokami
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Junko Tanaka
- Department of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tatsuya Kanto
- Hepatitis Information Center, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
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Nishida N, Ohashi J, Suda G, Chiyoda T, Tamaki N, Tomiyama T, Ogasawara S, Sugiyama M, Kawai Y, Khor SS, Nagasaki M, Fujimoto A, Tsuchiura T, Ishikawa M, Matsuda K, Yano H, Yoshizumi T, Izumi N, Hasegawa K, Sakamoto N, Mizokami M, Tokunaga K. Prediction Model with HLA-A*33:03 Reveals Number of Days to Develop Liver Cancer from Blood Test. Int J Mol Sci 2023; 24:ijms24054761. [PMID: 36902191 PMCID: PMC10003621 DOI: 10.3390/ijms24054761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/23/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
The development of liver cancer in patients with hepatitis B is a major problem, and several models have been reported to predict the development of liver cancer. However, no predictive model involving human genetic factors has been reported to date. For the items incorporated in the prediction model reported so far, we selected items that were significant in predicting liver carcinogenesis in Japanese patients with hepatitis B and constructed a prediction model of liver carcinogenesis by the Cox proportional hazard model with the addition of Human Leukocyte Antigen (HLA) genotypes. The model, which included four items-sex, age at the time of examination, alpha-fetoprotein level (log10AFP) and presence or absence of HLA-A*33:03-revealed an area under the receiver operating characteristic curve (AUROC) of 0.862 for HCC prediction within 1 year and an AUROC of 0.863 within 3 years. A 1000 repeated validation test resulted in a C-index of 0.75 or higher, or sensitivity of 0.70 or higher, indicating that this predictive model can distinguish those at high risk of developing liver cancer within a few years with high accuracy. The prediction model constructed in this study, which can distinguish between chronic hepatitis B patients who develop hepatocellular carcinoma (HCC) early and those who develop HCC late or not, is clinically meaningful.
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Affiliation(s)
- Nao Nishida
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa 272-8516, Japan
- Department of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
- Correspondence: ; Tel.: +81-473723501
| | - Jun Ohashi
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan
| | - Takehiro Chiyoda
- Hepato-Biliary-Pancreatic Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino 180-8610, Japan
| | - Takahiro Tomiyama
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Sachiko Ogasawara
- Department of Pathology, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Masaya Sugiyama
- Department of Viral Pathogenesis and Controls, National Center for Global Health and Medicine, Ichikawa 272-8516, Japan
| | - Yosuke Kawai
- Genome Medical Science Project-Toyama, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | - Seik-Soon Khor
- Genome Medical Science Project-Toyama, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | - Masao Nagasaki
- Human Biosciences Unit for the Top Global Course Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8507, Japan
| | - Akihiro Fujimoto
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0003, Japan
| | - Takayo Tsuchiura
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa 272-8516, Japan
| | - Miyuki Ishikawa
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa 272-8516, Japan
| | - Koichi Matsuda
- Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 108-8639, Japan
| | - Hirohisa Yano
- Department of Pathology, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino 180-8610, Japan
| | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan
| | - Masashi Mizokami
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa 272-8516, Japan
| | - Katsushi Tokunaga
- Genome Medical Science Project-Toyama, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
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Practical forensic use of kinship determination using high-density SNP profiling based on a microarray platform, focusing on low-quantity DNA. Forensic Sci Int Genet 2022; 61:102752. [DOI: 10.1016/j.fsigen.2022.102752] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 07/16/2022] [Accepted: 07/27/2022] [Indexed: 11/20/2022]
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Ashouri S, Khor SS, Hitomi Y, Sawai H, Nishida N, Sugiyama M, Kawai Y, Posuwan N, Tangkijvanich P, Komolmit P, Tsuiji M, Shotelersuk V, Poovorawan Y, Mizokami M, Tokunaga K. Genome-Wide Association Study for Chronic Hepatitis B Infection in the Thai Population. Front Genet 2022; 13:887121. [PMID: 35769989 PMCID: PMC9234442 DOI: 10.3389/fgene.2022.887121] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 05/16/2022] [Indexed: 11/19/2022] Open
Abstract
To identify novel host genetic variants that predispose to hepatitis B virus (HBV) persistence, we performed the first genome-wide association study in the Thai population involving 318 cases of chronic hepatitis B and 309 healthy controls after quality control measures. We detected the genome-wide significant association of the HLA class II region (HLA-DPA1/DPB1, rs7770370, p-value = 7.71 × 10-10, OR = 0.49) with HBV chronicity. Subsequent HLA allele imputation revealed HLA-DPA1*01:03 (Pc = 1.21 × 10-6, OR = 0.53), HLA-DPB1*02:01 (Pc = 2.17 × 10-3, OR = 0.50), and HLA-DQB1*06:09 (Pc = 2.17 × 10-2, OR = 0.07) as protective alleles, and HLA-DPA1*02:02 (Pc = 6.32 × 10-5, OR = 1.63), HLA-DPB1*05:01 (Pc = 1.13 × 10-4, OR = 1.72), HLA-DPB1*13:01 (Pc = 4.68 × 10-2, OR = 1.60), and HLA-DQB1*03:03 (Pc = 1.11 × 10-3, OR = 1.84) as risk alleles for HBV persistence. We also detected suggestive associations in the PLSCR1 (rs35766154), PDLIM5 (rs62321986), SGPL1 (rs144998273), and MGST1 (rs1828682) loci. Among single-nucleotide polymorphisms in the PLSCR1 locus, rs1061307 was identified as the primary functional variant by in silico/in vitro functional analysis. In addition to replicating the association of the HLA class II region, we detected novel candidate loci that provide new insights into the pathophysiology of chronic hepatitis B.
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Affiliation(s)
- Saeideh Ashouri
- Genome Medical Science Project, National Center for Global Health and Medicine, Toyama, Tokyo,Japan
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Seik-Soon Khor
- Genome Medical Science Project, National Center for Global Health and Medicine, Toyama, Tokyo,Japan
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yuki Hitomi
- Department of Microbiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan
| | - Hiromi Sawai
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Nao Nishida
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Masaya Sugiyama
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Yosuke Kawai
- Genome Medical Science Project, National Center for Global Health and Medicine, Toyama, Tokyo,Japan
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Nawarat Posuwan
- Chulabhorn International College of Medicine, Thammasat University, Rangsit Campus, Pathum Thani, Thailand
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Piyawat Komolmit
- Center of Excellence in Liver Diseases, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
- Liver Fibrosis and Cirrhosis Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Makoto Tsuiji
- Department of Microbiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan
| | - Vorasuk Shotelersuk
- Department of Pediatrics, Center of Excellence for Medical Genomics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Masashi Mizokami
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Katsushi Tokunaga
- Genome Medical Science Project, National Center for Global Health and Medicine, Toyama, Tokyo,Japan
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Schreiber S, Honz M, Mamozai W, Kurktschiev P, Schiemann M, Witter K, Moore E, Zielinski C, Sette A, Protzer U, Wisskirchen K. Characterization of a library of 20 HBV-specific MHC class II-restricted T cell receptors. Mol Ther Methods Clin Dev 2021; 23:476-489. [PMID: 34853796 PMCID: PMC8605085 DOI: 10.1016/j.omtm.2021.10.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/27/2021] [Accepted: 10/27/2021] [Indexed: 02/07/2023]
Abstract
CD4+ T cells play an important role in the immune response against cancer and infectious diseases. However, mechanistic details of their helper function in hepatitis B virus (HBV) infection in particular, or their advantage for adoptive T cell therapy remain poorly understood as experimental and therapeutic tools are missing. Therefore, we identified, cloned, and characterized a comprehensive library of 20 MHC class II-restricted HBV-specific T cell receptors (TCRs) from donors with acute or resolved HBV infection. The TCRs were restricted by nine different MHC II molecules and specific for eight different epitopes derived from intracellularly processed HBV envelope, core, and polymerase proteins. Retroviral transduction resulted in a robust expression of all TCRs on primary T cells. A high functional avidity was measured for all TCRs specific for epitopes S17, S21, S36, and P774 (half-maximal effective concentration [EC50] <10 nM), or C61 and preS9 (EC50 <100 nM). Eight TCRs recognized peptide variants of HBV genotypes A to D. Both CD4+ and CD8+ T cells transduced with the MHC II-restricted TCRs were polyfunctional, producing interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, and granzyme B (GrzB), and killed peptide-loaded target cells. Our set of MHC class II-restricted TCRs represents an important tool for elucidating CD4+ T cell help in viral infection with potential benefit for T cell therapy.
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Association analysis of KIR/HLA genotype with liver cirrhosis, hepatocellular carcinoma, and NUC freedom in chronic hepatitis B patients. Sci Rep 2021; 11:21424. [PMID: 34728722 PMCID: PMC8563771 DOI: 10.1038/s41598-021-01014-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 10/21/2021] [Indexed: 11/21/2022] Open
Abstract
Natural killer cells are modulated through the binding of killer cell immunoglobulin-like receptors (KIRs) with human leukocyte antigen (HLA) class I ligands. This study investigated the association of KIR/HLA pairs with progression to liver cirrhosis, hepatocellular carcinoma (HCC) development, and nucleot(s)ide (NUC) treatment freedom in hepatitis B virus (HBV) infection. KIR, HLA-Bw, and HLA-C were genotyped in 280 Japanese HBV patients for clinical comparisons. No significant associations of KIR/HLA pairs were detected in terms of liver cirrhosis development. The KIR2DS3 positive rate was significantly higher in patients with HCC (n = 39) than in those without (n = 241) [30.8% vs. 14.9%, odds ratio (OR) 2.53, P = 0.015]. The KIR3DL1/HLA-Bw4 pair rate was significantly lower in the NUC freedom group (n = 20) than in the NUC continue group (n = 114) (25.0% vs. 52.6%, OR 0.30, P = 0.042). In conclusion, this study indicated remarkable associations of KIR/HLA with HCC development (KIR2DS3) and freedom from NUC therapy (KIR3DL1/HLA-Bw4) in HBV patients, although the number of cases was insufficient for statistical purposes. Additional multi-center analyses of larger groups are needed to clarify whether KIR/HLA pairs play a role in HBV patient status.
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Variation and expression of HLA-DPB1 gene in HBV infection. Immunogenetics 2021; 73:253-261. [PMID: 33710355 DOI: 10.1007/s00251-021-01213-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 03/01/2021] [Indexed: 12/24/2022]
Abstract
Hepatitis B virus (HBV) affects approximately 68 million people in China, and 10-15% of adults infected with HBV develop chronic hepatitis B, liver cirrhosis, liver failure or hepatocellular carcinoma (HCC). HLA-DPB1 gene polymorphism and expression have been shown to be associated with HBV infection susceptibility and spontaneous clearance. The aim of this study is to evaluate the role of HLA-DPB1 gene polymorphism in HBV infection. HLA-DPB1 and rs9277535 polymorphisms were investigated in 259 patients with HBV infection and 442 healthy controls (HCs) using sequence-based typing. The mRNA of HLA-DPB1 was measured by real-time polymerase chain reaction. HLA-DPB1 genes and rs9277535 polymorphisms were all associated with HBV infection in the Sichuan Han population. rs9277535A and HLA-DPB1*04:02 played a protective role against HBV infection. rs9277535G and DPB1*05:01 were associated with susceptibility to HBV infection. rs9277535GG had significantly higher HLA-DPB1 mRNA expression in the HBV infection group compared with the HC group. HLA-DPB1*05:01 and HLA-DPB1*21:01 had significantly lower mRNA expression in the HBV infection group compared with the HC group. The meta-analysis revealed that HLA-DPB1*02:01, HLA-DPB1*02:02, HAL-DPB1*04:01 and HLA-DPB1*04:02 protected against HBV infection, while HLA-DPB1*05:01, HLA-DPB1*09:01, and HLA-DPB1*13:01 were risk factors for susceptibility to HBV infection. HLA-DPB1*02:01, HLA-DPB1*02:02, and HLA-DPB1*04:01 were associated with HBV spontaneous clearance, while HLA-DPB1*05:01 was associated with chronic HBV infection. HLA-DPB1 alleles and rs9277535 have a major effect on the risk of HBV infection, and HBV infection is associated with lower HLA-DPB1 expression. HLA-DPB1 alleles have an important role in HBV susceptibility and spontaneous clearance.
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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.
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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.
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12
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Huang YH, Liao SF, Khor SS, Lin YJ, Chen HY, Chang YH, Huang YH, Lu SN, Lee HW, Ko WY, Huang C, Liu PC, Chen YJ, Wu PF, Chu HW, Wu PE, Tokunaga K, Shen CY, Lee MH. Large-scale genome-wide association study identifies HLA class II variants associated with chronic HBV infection: a study from Taiwan Biobank. Aliment Pharmacol Ther 2020; 52:682-691. [PMID: 32573827 DOI: 10.1111/apt.15887] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 05/07/2020] [Accepted: 05/25/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) infection is a great health burden with geographical variations. AIMS To explore genetic variants associated with chronic HBV infection. METHODS The study included 15 352 participants seropositive for HBV core antibodies in Taiwan Biobank. Among them, 2591 (16.9%) seropositive for HBV surface antigen (HBsAg) were defined as having chronic HBV infection. All participants were examined for whole-genome genotyping by Axiom-Taiwan Biobank Array. The human leucocyte antigen (HLA) imputation was performed after identification of the variants within the region. Logistic regressions were used to estimate odds ratios (ORs) with 95% confidence intervals. Correlations of different HLA allele frequencies with HBsAg seroprevalence were evaluated across worldwide populations by Pearson correlation coefficients. Epitope prediction was performed for HLA alleles using NetMHCIIpan method. RESULTS Located within a cluster of 450 single nucleotide polymorphisms in HLA class II, rs7770370 (P = 2.73 × 10-35 ) was significantly associated with HBV chronicity (Pcorrected < 8.6 × 10-8 ). Imputation analyses showed that HLA-DPA1*02:02 and HLA-DPB1*05:01 were associated with chronic HBV, with adjusted ORs of 1.43 (1.09-1.89) and 1.61 (1.29-2.01). These allele frequencies were positively correlated with global HBsAg seroprevalence, with R of 0.75 and 0.62 respectively (P < 0.05). HLA-DRB1*13:02, HLA-DQA1* 01:02 and HLA-DQB1*06:09 associated with HBV chronicity negatively, with adjusted ORs of 0.31 (0.17-0.58), 0.70 (0.56-0.87) and 0.33 (0.18-0.63). These HLA alleles had various binding affinities to the predicted epitopes derived from HBV nucleocapsid protein. CONCLUSIONS HLA class II variants are relevant for chronicity after HBV acquisition.
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Barquera R, Lamnidis TC, Lankapalli AK, Kocher A, Hernández-Zaragoza DI, Nelson EA, Zamora-Herrera AC, Ramallo P, Bernal-Felipe N, Immel A, Bos K, Acuña-Alonzo V, Barbieri C, Roberts P, Herbig A, Kühnert D, Márquez-Morfín L, Krause J. Origin and Health Status of First-Generation Africans from Early Colonial Mexico. Curr Biol 2020; 30:2078-2091.e11. [PMID: 32359431 DOI: 10.1016/j.cub.2020.04.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 03/03/2020] [Accepted: 04/01/2020] [Indexed: 02/07/2023]
Abstract
The forced relocation of several thousand Africans during Mexico's historic period has so far been documented mostly through archival sources, which provide only sparse detail on their origins and lived experience. Here, we employ a bioarchaeological approach to explore the life history of three 16th century Africans from a mass burial at the San José de los Naturales Royal Hospital in Mexico City. Our approach draws together ancient genomic data, osteological analysis, strontium isotope data from tooth enamel, δ13C and δ15N isotope data from dentine, and ethnohistorical information to reveal unprecedented detail on their origins and health. Analyses of skeletal features, radiogenic isotopes, and genetic data from uniparental, genome-wide, and human leukocyte antigen (HLA) markers are consistent with a Sub-Saharan African origin for all three individuals. Complete genomes of Treponema pallidum sub. pertenue (causative agent of yaws) and hepatitis B virus (HBV) recovered from these individuals provide insight into their health as related to infectious disease. Phylogenetic analysis of both pathogens reveals their close relationship to strains circulating in current West African populations, lending support to their origins in this region. The further relationship between the treponemal genome retrieved and a treponemal genome previously typed in an individual from Colonial Mexico highlights the role of the transatlantic slave trade in the introduction and dissemination of pathogens into the New World. Putting together all lines of evidence, we were able to create a biological portrait of three individuals whose life stories have long been silenced by disreputable historical events.
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Affiliation(s)
- Rodrigo Barquera
- Department of Archaeogenetics (DAG), Max-Planck Institute for the Science of Human History (MPI-SHH), Kahlaische Str. 10, 07745 Jena, Germany; Molecular Genetics Laboratory, Escuela Nacional de Antropología e Historia (ENAH), Periférico Sur y Zapote s/n. Col. Isidro Fabela, Tlalpan, 14030 Mexico City, Mexico
| | - Thiseas C Lamnidis
- Department of Archaeogenetics (DAG), Max-Planck Institute for the Science of Human History (MPI-SHH), Kahlaische Str. 10, 07745 Jena, Germany
| | - Aditya Kumar Lankapalli
- Department of Archaeogenetics (DAG), Max-Planck Institute for the Science of Human History (MPI-SHH), Kahlaische Str. 10, 07745 Jena, Germany
| | - Arthur Kocher
- Transmission, Infection, Diversification & Evolution Group (TIDE), Max-Planck Institute for the Science of Human History (MPI-SHH), Kahlaische Str. 10, 07745 Jena, Germany
| | - Diana I Hernández-Zaragoza
- Molecular Genetics Laboratory, Escuela Nacional de Antropología e Historia (ENAH), Periférico Sur y Zapote s/n. Col. Isidro Fabela, Tlalpan, 14030 Mexico City, Mexico; Immunogenetics Unit, Técnicas Genéticas Aplicadas a la Clínica (TGAC), Calz. del Hueso 714, Coapa, Los Sauces, Coyoacán, 04940 Mexico City, CDMX, Mexico
| | - Elizabeth A Nelson
- Department of Archaeogenetics (DAG), Max-Planck Institute for the Science of Human History (MPI-SHH), Kahlaische Str. 10, 07745 Jena, Germany; Institute for the Archaeological Sciences, University of Tübingen, Geschwister-Scholl-Platz, 72074 Tübingen, Germany
| | - Adriana C Zamora-Herrera
- Osteology Laboratory, Post Graduate Studies Division, Escuela Nacional de Antropología e Historia (ENAH), Periférico Sur y Zapote s/n. Col. Isidro Fabela, Tlalpan, 14030 Mexico City, Mexico
| | - Patxi Ramallo
- Department of Archaeology (DA), Max-Planck Institute for the Science of Human History (MPI-SHH), Kahlaische Str. 10, 07745 Jena, Germany; Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Arriola Pasealekua, 2, 20018 Donostia, Gipuzkoa, Spain
| | - Natalia Bernal-Felipe
- Escuela Nacional de Antropología e Historia (ENAH), Periférico Sur y Zapote s/n. Col. Isidro Fabela, Tlalpan, 14030 Mexico City, Mexico
| | - Alexander Immel
- Department of Archaeogenetics (DAG), Max-Planck Institute for the Science of Human History (MPI-SHH), Kahlaische Str. 10, 07745 Jena, Germany; Institute of Clinical Molecular Biology, Kiel University, Rosalind-Franklin-Straße 12, 24105 Kiel, Germany
| | - Kirsten Bos
- Department of Archaeogenetics (DAG), Max-Planck Institute for the Science of Human History (MPI-SHH), Kahlaische Str. 10, 07745 Jena, Germany
| | - Víctor Acuña-Alonzo
- Molecular Genetics Laboratory, Escuela Nacional de Antropología e Historia (ENAH), Periférico Sur y Zapote s/n. Col. Isidro Fabela, Tlalpan, 14030 Mexico City, Mexico
| | - Chiara Barbieri
- Department of Linguistic and Cultural Evolution (DLCE), Max-Planck Institute for the Science of Human History (MPI-SHH), Kahlaische Str. 10, 07745 Jena, Germany; Department of Evolutionary Biology and Environmental Studies, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland
| | - Patrick Roberts
- Department of Archaeology (DA), Max-Planck Institute for the Science of Human History (MPI-SHH), Kahlaische Str. 10, 07745 Jena, Germany
| | - Alexander Herbig
- Department of Archaeogenetics (DAG), Max-Planck Institute for the Science of Human History (MPI-SHH), Kahlaische Str. 10, 07745 Jena, Germany
| | - Denise Kühnert
- Transmission, Infection, Diversification & Evolution Group (TIDE), Max-Planck Institute for the Science of Human History (MPI-SHH), Kahlaische Str. 10, 07745 Jena, Germany.
| | - Lourdes Márquez-Morfín
- Osteology Laboratory, Post Graduate Studies Division, Escuela Nacional de Antropología e Historia (ENAH), Periférico Sur y Zapote s/n. Col. Isidro Fabela, Tlalpan, 14030 Mexico City, Mexico.
| | - Johannes Krause
- Department of Archaeogenetics (DAG), Max-Planck Institute for the Science of Human History (MPI-SHH), Kahlaische Str. 10, 07745 Jena, Germany.
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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.
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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
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15
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Wang X, Cao X, Zhang W, Zhang L, Lu L, Li X, El‐Ashram S, Wu J, Chen C. Association of human leukocyte antigens-DQB2/DPA1/DPB1 polymorphism and pulmonary tuberculosis in the Chinese Uygur population. Mol Genet Genomic Med 2019; 7:e544. [PMID: 30600606 PMCID: PMC6418356 DOI: 10.1002/mgg3.544] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 11/01/2018] [Accepted: 12/02/2018] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Tuberculosis (TB) is the second-leading cause of death globally. Genetic polymorphisms in human leukocyte antigens (HLA)-DQB2, HLA-DPA1, and HLA-DPB1 may partly explain individual differences in TB susceptibility. METHODS We performed a hospital-based case-control study to assess the genetic influence of single-nucleotide polymorphisms (SNPs) in the HLA (HLA-DPA, HLA-DPB, and HLA-DQB) on the development of TB. There were 248 TB-infected cases and 340 healthy controls in this study. RESULTS The HLA-DQB2 rs7453920 genotype GG was applied as the reference group, the GA genotype was related to a considerably magnified risk of TB (GA vs. GG: adjusted OR = 1.547, 95% CI = 1.039-2.304, p = 0.032). Nevertheless, the other two SNPs were not associated with TB risk. Stratified analyses suggested that tobacco was associated with an increased risk of TB in HLA-DQB2 rs7453920 G>A. CONCLUSION These results suggested that the functional HLA-DQB2 rs7453920 G>A polymorphism may contribute to the genetic susceptibility to TB. Nevertheless, the results were based on a limited sample size, and larger well-designed studies are expected to confirm these preliminary findings.
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Affiliation(s)
- Xue Wang
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases Cooperated by Education Ministry with Xinjiang ProvinceShihezi UniversityShiheziChina
| | - Xudong Cao
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases Cooperated by Education Ministry with Xinjiang ProvinceShihezi UniversityShiheziChina
| | - Wanjiang Zhang
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases Cooperated by Education Ministry with Xinjiang ProvinceShihezi UniversityShiheziChina
| | - Le Zhang
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases Cooperated by Education Ministry with Xinjiang ProvinceShihezi UniversityShiheziChina
| | - Lijun Lu
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases Cooperated by Education Ministry with Xinjiang ProvinceShihezi UniversityShiheziChina
| | - Xinyue Li
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases Cooperated by Education Ministry with Xinjiang ProvinceShihezi UniversityShiheziChina
| | - Saeed El‐Ashram
- College of Life Science and EngineeringFoshan UniversityFoshanChina
- Faculty of ScienceKafrelsheikh Universitykafr El-SheikhEgypt
| | - Jiangdong Wu
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases Cooperated by Education Ministry with Xinjiang ProvinceShihezi UniversityShiheziChina
| | - Chuangfu Chen
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases Cooperated by Education Ministry with Xinjiang ProvinceShihezi UniversityShiheziChina
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Omae Y, Tokunaga K. Genetics of Infectious Diseases. GENOME-WIDE ASSOCIATION STUDIES 2019:145-174. [DOI: 10.1007/978-981-13-8177-5_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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17
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Ou G, Liu X, Yang L, Yu H, Ji X, Liu F, Xu H, Qian L, Wang J, Liu Z. Relationship between HLA-DPA1 mRNA expression and susceptibility to hepatitis B. J Viral Hepat 2019; 26:155-161. [PMID: 30267609 DOI: 10.1111/jvh.13012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 09/07/2018] [Indexed: 12/12/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is influenced by both viral and host factors. In genome-wide association studies, the human leucocyte antigen HLA-DPA1 and related polymorphism rs3077 were found to be associated with susceptibility to and spontaneous clearance of HBV infection. Here, we evaluated the association between HLA-DPA1 mRNA expression and the risk of HBV infection. HLA-DPA1 and rs3077 polymorphisms were investigated in 169 patients with chronic HBV and 217 healthy controls (HCs) from Sichuan Han blood donors using sequence-based typing and meta-analysis for HLA-DPA1 alleles. HLA-DPA1 mRNA levels were measured by real-time polymerase chain reaction. The results showed that HLA-DPA1 and rs3077 were associated with HBV infection in the Sichuan population. Rs3077T and DPA1*01:03 played protective roles in HBV infection, and rs3077C and DPA1*02:02 increased susceptibility to HBV infection. We found that the HLA-DPA1 mRNA expression was decreased in the CHB group; in particular, the 3077CT, 3077TT, DPA1*01:03 and DPA1*02:01 alleles showed a significant decrease. Our results demonstrated, for the first time, that expression of HLA-DPA1 alleles and rs3077 affected the risk of HBV infection. Genotypes with lower HLA-DPA1 expression had a greater susceptibility to HBV infection. Thus, further independent studies are needed to strengthen the associations of these polymorphisms with susceptibility to and clearance of HBV infection in Chinese populations.
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Affiliation(s)
- Guojin Ou
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China.,Clinical Blood Transfusion Research Center, Institute of Blood Transfusion, CAMS & PUMC, Chengdu, China.,Key Laboratory of Transfusion Adverse Reactions, CAMS, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, (Sichuan University), Ministry of Education, Chengdu, China
| | - Xiao Liu
- Deyang People's Hospital, Deyang, China
| | - Liu Yang
- Tianfu New District People's Hospital, Chengdu, China
| | - Hao Yu
- Clinical Blood Transfusion Research Center, Institute of Blood Transfusion, CAMS & PUMC, Chengdu, China.,Key Laboratory of Transfusion Adverse Reactions, CAMS, Chengdu, China
| | - Xin Ji
- Clinical Blood Transfusion Research Center, Institute of Blood Transfusion, CAMS & PUMC, Chengdu, China.,Key Laboratory of Transfusion Adverse Reactions, CAMS, Chengdu, China
| | - Fan Liu
- Clinical Blood Transfusion Research Center, Institute of Blood Transfusion, CAMS & PUMC, Chengdu, China.,Key Laboratory of Transfusion Adverse Reactions, CAMS, Chengdu, China
| | - Haixia Xu
- Clinical Blood Transfusion Research Center, Institute of Blood Transfusion, CAMS & PUMC, Chengdu, China.,Key Laboratory of Transfusion Adverse Reactions, CAMS, Chengdu, China
| | | | - Jue Wang
- Clinical Blood Transfusion Research Center, Institute of Blood Transfusion, CAMS & PUMC, Chengdu, China.,Key Laboratory of Transfusion Adverse Reactions, CAMS, Chengdu, China
| | - Zhong Liu
- Clinical Blood Transfusion Research Center, Institute of Blood Transfusion, CAMS & PUMC, Chengdu, China.,Key Laboratory of Transfusion Adverse Reactions, CAMS, Chengdu, China
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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.
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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
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19
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Progress of research on the immune tolerance of chronic HBV infection. INFECTION INTERNATIONAL 2018. [DOI: 10.2478/ii-2018-0026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Immune tolerance is a specific lack or negative response of T and B lymphocytes to antigen. According to different formation periods, immune tolerance can be divided into central and peripheral tolerances. The immune tolerance of the body to hepatitis B virus (HBV) after infection is the main cause of chronic HBV infection. In this paper, the functional defects of hepatitis B virus e antigen and dendritic cells, hyporesponsiveness of cytotoxic T lymphocyte, variation of helper T lymphocytes and cytokines, HBV genotype and genome, and the role of host gene polymorphism in the formation of immune tolerance in chronic HBV infection and its related research progress are introduced briefly.
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20
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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: 46] [Impact Index Per Article: 6.6] [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, depending on the success or failure of immune response to HBV. 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.
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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
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Kim TH, Lee EJ, Choi JH, Yim SY, Lee S, Kang J, Lee YR, Lee HA, Choi HS, Kim ES, Keum B, Seo YS, Yim HJ, Jeen YT, Chun HJ, Lee HS, Kim CD, Woo HG, Um SH. Identification of novel susceptibility loci associated with hepatitis B surface antigen seroclearance in chronic hepatitis B. PLoS One 2018; 13:e0199094. [PMID: 29975729 PMCID: PMC6033413 DOI: 10.1371/journal.pone.0199094] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 05/31/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND/AIMS The seroclearance of hepatitis B virus (HBV) surface antigen (HBsAg) is regarded as a functional cure of chronic hepatitis B (CHB) although it occurs rarely. Recently, several genome-wide association studies (GWASs) revealed various genetic alterations related to the clinical course of HBV infection. However, all of these studies focused on the progression of HBV infection to chronicity and had limited application because of the heterogeneity of HBV genotypes. In the present study, we aimed to determine susceptibility genetic markers for seroclearance of HBsAg in CHB patients with a homogenous viral genotype. METHODS One hundred patients with CHB who had experienced HBsAg seroclearance before 60 years of age and another 100 with CHB showing high serum levels of HBsAg even after 60 years of age were enrolled. Extreme-phenotype GWAS was conducted using blood samples of participants. RESULTS We identified three single nucleotide polymorphisms, rs7944135 (P = 4.17 × 10-6, odds ratio [OR] = 4.16, 95% confidence interval [CI] = 2.27-7.63) at 11q12.1, rs171941 (P = 3.52×10-6, OR = 3.69, 95% CI = 2.13-6.42) at 5q14.1, and rs6462008 (P = 3.40×10-6, OR = 0.34, 95% CI = 0.22-0.54) at 7p15.2 as novel susceptibility loci associated with HBsAg seroclearance in patients with CHB. The flanking genes at these loci including MPEG1, DTX4, MTX3, and HOXA13 were suggested to have functional significance. In addition, through functional analysis, CXCL13 was also presumed to be related. CONCLUSIONS To the best of our knowledge, this study is the first GWAS regarding the seroclearance of HBsAg in CHB patients. We identify new susceptibility loci for cure of CHB, providing new insights into its pathophysiology.
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Affiliation(s)
- Tae Hyung Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Eun-Ju Lee
- Department of Physiology, Ajou University School of Medicine, Suwon, Korea
| | - Ji-Hye Choi
- Department of Physiology, Ajou University School of Medicine, Suwon, Korea
- Department of Biomedical Science, Graduate School, Ajou University, Suwon, Korea
| | - Sun Young Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Sunwon Lee
- Department of Computer Science and Engineering, Korea University College of Informatics, Seoul, Korea
| | - Jaewoo Kang
- Department of Computer Science and Engineering, Korea University College of Informatics, Seoul, Korea
| | - Yoo Ra Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Han Ah Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hyuk Soon Choi
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Eun Sun Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Bora Keum
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Yeon Seok Seo
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hyung Joon Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Yoon Tae Jeen
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hoon Jai Chun
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hong Sik Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Chang Duck Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Hyun Goo Woo
- Department of Physiology, Ajou University School of Medicine, Suwon, Korea
- Department of Biomedical Science, Graduate School, Ajou University, Suwon, Korea
- * E-mail: (HGW); (SHU)
| | - Soon Ho Um
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
- * E-mail: (HGW); (SHU)
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22
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Sawai H, Nishida N, Khor SS, Honda M, Sugiyama M, Baba N, Yamada K, Sawada N, Tsugane S, Koike K, Kondo Y, Yatsuhashi H, Nagaoka S, Taketomi A, Fukai M, Kurosaki M, Izumi N, Kang JH, Murata K, Hino K, Nishina S, Matsumoto A, Tanaka E, Sakamoto N, Ogawa K, Yamamoto K, Tamori A, Yokosuka O, Kanda T, Sakaida I, Itoh Y, Eguchi Y, Oeda S, Mochida S, Yuen MF, Seto WK, Poovorawan Y, Posuwan N, Mizokami M, Tokunaga K. Genome-wide association study identified new susceptible genetic variants in HLA class I region for hepatitis B virus-related hepatocellular carcinoma. Sci Rep 2018; 8:7958. [PMID: 29784950 PMCID: PMC5962604 DOI: 10.1038/s41598-018-26217-7] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Accepted: 05/02/2018] [Indexed: 12/11/2022] Open
Abstract
We have performed a genome-wide association study (GWAS) including 473 Japanese HBV (hepatitis B virus)-positive HCC (hepatocellular carcinoma) patients and 516 HBV carriers including chronic hepatitis and asymptomatic carrier individuals to identify new host genetic factors associated with HBV-derived HCC in Japanese and other East Asian populations. We identified 65 SNPs with P values < 10-4 located within the HLA class I region and three SNPs were genotyped in three independent population-based replication sets. Meta-analysis confirmed the association of the three SNPs (rs2523961: OR = 1.73, P = 7.50 × 10-12; rs1110446: OR = 1.79, P = 1.66 × 10-13; and rs3094137: OR = 1.73, P = 7.09 × 10-9). We then performed two-field HLA genotype imputation for six HLA loci using genotyping data to investigate the association between HLA alleles and HCC. HLA allele association testing revealed that HLA-A * 33:03 (OR = 1.97, P = 4.58 × 10-4) was significantly associated with disease progression to HCC. Conditioning analysis of each of the three SNPs on the HLA class I region abolished the association of HLA-A*33:03 with disease progression to HCC. However, conditioning the HLA allele could not eliminate the association of the three SNPs, suggesting that additional genetic factors may exist in the HLA class I region.
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Affiliation(s)
- Hiromi Sawai
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Nao Nishida
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Seik-Soon Khor
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Masaya Sugiyama
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Natsumi Baba
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kayoko Yamada
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Norie Sawada
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Shoichiro Tsugane
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yuji Kondo
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Yatsuhashi
- Clinical Research Center, National Nagasaki Medical Center, Nagasaki, Japan
| | - Shinya Nagaoka
- Clinical Research Center, National Nagasaki Medical Center, Nagasaki, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Moto Fukai
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Masayuki Kurosaki
- Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Namiki Izumi
- Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Jong-Hon Kang
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Kazumoto Murata
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Japan
- Department of Gastroenterology, Graduate School of Medical Sciences, International University of Health and Welfare, Narita, Japan
| | - Keisuke Hino
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan
| | - Sohji Nishina
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan
| | - Akihiro Matsumoto
- Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Eiji Tanaka
- Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Kazuhide Yamamoto
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Akihiro Tamori
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Isao Sakaida
- Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | | | - Satoshi Oeda
- Liver center, Saga University Hospital, Saga, Japan
| | - Satoshi Mochida
- Division of Gastroenterology and Hepatology, Saitama Medical University, Saitama, Japan
| | - Man-Fung Yuen
- Department of Medicine and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
| | - Wai-Kay Seto
- Department of Medicine and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Nawarat Posuwan
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Masashi Mizokami
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Katsushi Tokunaga
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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23
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Virological and Clinical Characteristics of Hepatitis B Virus Genotype A. J Gastroenterol 2018; 53:18-26. [PMID: 28687901 DOI: 10.1007/s00535-017-1367-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 06/30/2017] [Indexed: 02/04/2023]
Abstract
Hepatitis B virus (HBV) infection is one of the most prevalent chronic viral infections in humans. The overall prevalence of hepatitis B surface antigen (HBsAg) is reported to be 3.6%; however, it varies depending upon the geographic area. HBV is classified into ten genotypes (A through J) on the basis of an intergroup genomic divergence of > 8%. Specifically, HBV genotype A exhibits several unique virological and clinical characteristics and can be further classified into seven subtypes. Among them, subtype A2 or Ae (A2/[e]) is occasionally responsible for nosocomial infection and among homosexual males. Regarding virological factors, the G1896A precore mutation is rarely observed in genotype A as it would disrupt an essential stem-loop structure in the ε signal essential for pregenomic RNA packaging. HBV genotype A also harbors a 6-nucleotide C-terminal insertion in the hepatitis B-e antigen (HBeAg) precursor, resulting in a variable-length HBeAg protein product observed in serum of positive patients. These molecular traits likely contribute to the specific clinical presentation of genotype A-infected patients, such as mild acute hepatitis B (AHB), longer persistence of HBsAg positivity in AHB, and increased chronicity after AHB in adults. However, genotype A shows a better response to interferon than other genotypes in chronic hepatitis B patients. Here, we review the virological and clinical characteristics of HBV genotype A that will be useful in elucidating the association among persistent viral infection, host genetic factors, and treatment in future studies.
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24
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Bigdeli TB, Ripke S, Peterson RE, Trzaskowski M, Bacanu SA, Abdellaoui A, Andlauer TFM, Beekman ATF, Berger K, Blackwood DHR, Boomsma DI, Breen G, Buttenschøn HN, Byrne EM, Cichon S, Clarke TK, Couvy-Duchesne B, Craddock N, de Geus EJC, Degenhardt F, Dunn EC, Edwards AC, Fanous AH, Forstner AJ, Frank J, Gill M, Gordon SD, Grabe HJ, Hamilton SP, Hardiman O, Hayward C, Heath AC, Henders AK, Herms S, Hickie IB, Hoffmann P, Homuth G, Hottenga JJ, Ising M, Jansen R, Kloiber S, Knowles JA, Lang M, Li QS, Lucae S, MacIntyre DJ, Madden PAF, Martin NG, McGrath PJ, McGuffin P, McIntosh AM, Medland SE, Mehta D, Middeldorp CM, Milaneschi Y, Montgomery GW, Mors O, Müller-Myhsok B, Nauck M, Nyholt DR, Nöthen MM, Owen MJ, Penninx BWJH, Pergadia ML, Perlis RH, Peyrot WJ, Porteous DJ, Potash JB, Rice JP, Rietschel M, Riley BP, Rivera M, Schoevers R, Schulze TG, Shi J, Shyn SI, Smit JH, Smoller JW, Streit F, Strohmaier J, Teumer A, Treutlein J, Van der Auwera S, van Grootheest G, van Hemert AM, Völzke H, Webb BT, Weissman MM, Wellmann J, Willemsen G, Witt SH, Levinson DF, Lewis CM, Wray NR, Flint J, Sullivan PF, Kendler KS. Genetic effects influencing risk for major depressive disorder in China and Europe. Transl Psychiatry 2017; 7:e1074. [PMID: 28350396 PMCID: PMC5404611 DOI: 10.1038/tp.2016.292] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2016] [Accepted: 11/27/2016] [Indexed: 11/24/2022] Open
Abstract
Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor=8.08) but failed to replicate in an independent European sample (P=0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.
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Affiliation(s)
- T B Bigdeli
- Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - S Ripke
- Department of Psychiatry, Charite Universitatsmedizin Berlin Campus Benjamin Franklin, Berlin, Germany
- Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
- Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
| | - R E Peterson
- Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - M Trzaskowski
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
| | - S-A Bacanu
- Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - A Abdellaoui
- Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - T F M Andlauer
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - A T F Beekman
- Department of Psychiatry, VU University Medical Center and GGZ inGeest, Amsterdam, The Netherlands
| | - K Berger
- Institute of Epidemiology and Social Medicine, University of Muenster, Münster, Germany
| | - D H R Blackwood
- Division of Psychiatry, University of Edinburgh, Edinburgh, UK
| | - D I Boomsma
- Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - G Breen
- King's College London, NIHR BRC for Mental Health, London, UK
- King's College London, MRC Social Genetic and Developmental Psychiatry Centre, London, UK
| | - H N Buttenschøn
- Department of Clinical Medicine, Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark
| | - E M Byrne
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
| | - S Cichon
- Department of Biomedicine, University of Basel, Basel, Switzerland
- Division of Medical Genetics, University of Basel, Basel, Switzerland
- Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Jülich, Germany
- Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - T-K Clarke
- Division of Psychiatry, University of Edinburgh, Edinburgh, UK
| | - B Couvy-Duchesne
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Centre for Advanced Imaging, University of Queensland, Brisbane, QLD, Australia
| | - N Craddock
- Department of Psychological Medicine, Cardiff University, Cardiff, UK
| | - E J C de Geus
- Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- EMGO+ Institute, VU University Medical Center, Amsterdam, The Netherlands
| | - F Degenhardt
- Institute of Human Genetics, University of Bonn, Bonn, Germany
- Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany
| | - E C Dunn
- Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA
- Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
- Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
| | - A C Edwards
- Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - A H Fanous
- Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn, NY, USA
| | - A J Forstner
- Institute of Human Genetics, University of Bonn, Bonn, Germany
- Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany
| | - J Frank
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - M Gill
- Department of Psychiatry, Trinity College Dublin, Dublin, Ireland
| | - S D Gordon
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - H J Grabe
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
| | - S P Hamilton
- Department of Psychiatry, Kaiser-Permanente Northern California, San Fransisco, CA, USA
| | - O Hardiman
- Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland
| | - C Hayward
- Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - A C Heath
- Department of Psychiatry, Washington University in Saint Louis School of Medicine, St Louis, MO, USA
| | - A K Henders
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
| | - S Herms
- Institute of Human Genetics, University of Bonn, Bonn, Germany
- Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany
- Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - I B Hickie
- Brain and Mind Research Institute, University of Sydney, Sydney, NSW, Australia
| | - P Hoffmann
- Institute of Human Genetics, University of Bonn, Bonn, Germany
- Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany
- Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - G Homuth
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany
| | - J-J Hottenga
- Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - M Ising
- Max Planck Institute of Psychiatry, Munich, Germany
| | - R Jansen
- Department of Psychiatry, VU University Medical Center and GGZ inGeest, Amsterdam, The Netherlands
| | - S Kloiber
- Max Planck Institute of Psychiatry, Munich, Germany
| | - J A Knowles
- Department of Psychiatry and The Behavioral Sciences, University of Southern California, Los Angeles, CA, USA
| | - M Lang
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - Q S Li
- Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Titusville, NJ, USA
| | - S Lucae
- Max Planck Institute of Psychiatry, Munich, Germany
| | - D J MacIntyre
- Division of Psychiatry, University of Edinburgh, Edinburgh, UK
| | - P A F Madden
- Department of Psychiatry, Washington University in Saint Louis School of Medicine, St Louis, MO, USA
| | - N G Martin
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- School of Psychology, University of Queensland, Brisbane, QLD, Australia
| | - P J McGrath
- Department of Psychiatry, New York State Psychiatric Institute, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - P McGuffin
- King's College London, MRC Social Genetic and Developmental Psychiatry Centre, London, UK
| | - A M McIntosh
- Division of Psychiatry, University of Edinburgh, Edinburgh, UK
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
| | - S E Medland
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - D Mehta
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
| | - C M Middeldorp
- Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Y Milaneschi
- Department of Psychiatry, VU University Medical Center and GGZ inGeest, Amsterdam, The Netherlands
| | - G W Montgomery
- Institute for Molecular Biology, University of Queensland, Brisbane, QLD, Australia
| | - O Mors
- Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark
| | - B Müller-Myhsok
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
| | - M Nauck
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
| | - D R Nyholt
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
| | - M M Nöthen
- Institute of Human Genetics, University of Bonn, Bonn, Germany
- Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany
| | - M J Owen
- MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK
| | - B W J H Penninx
- Department of Psychiatry, VU University Medical Center and GGZ inGeest, Amsterdam, The Netherlands
| | - M L Pergadia
- Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA
| | - R H Perlis
- Department of Psychiatry, Harvard Medical School, Boston, MA, USA
- Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
| | - W J Peyrot
- Department of Psychiatry, VU University Medical Center and GGZ inGeest, Amsterdam, The Netherlands
| | - D J Porteous
- Medical Genetics Section, CGEM, IGMM, University of Edinburgh, Edinburgh, UK
| | - J B Potash
- Department of Psychiatry, University of Iowa, Iowa, IA, USA
| | - J P Rice
- Department of Psychiatry, Washington University in Saint Louis, St Louis, MO, USA
| | - M Rietschel
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - B P Riley
- Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - M Rivera
- Department of Biochemistry and Molecular Biology II, Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, Spain
- King's College London, MRC Social Genetic and Developmental Psychiatry Centre, London, UK
| | - R Schoevers
- Department of Psychiatry, University of Groningen, University of Medical Center Groningen, Groningen, The Netherlands
| | - T G Schulze
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
- Institute of Psychiatric Phenomics and Genomics, Medical Center of the University of Munich, Campus Innenstadt, Munich, Germany
- Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, The Netherlands
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA
- Human Genetics Branch, NIMH Division of Intramural Research Programs, Bethesda, MD, USA
| | - J Shi
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - S I Shyn
- Division of Psychiatry, Group Health, Seattle, WA, USA
| | - J H Smit
- Department of Psychiatry, VU University Medical Center and GGZ inGeest, Amsterdam, The Netherlands
| | - J W Smoller
- Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA
- Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
- Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
| | - F Streit
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - J Strohmaier
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - A Teumer
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - J Treutlein
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - S Van der Auwera
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
| | - G van Grootheest
- Department of Psychiatry, VU University Medical Center and GGZ inGeest, Amsterdam, The Netherlands
| | - A M van Hemert
- Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands
| | - H Völzke
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - B T Webb
- Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - M M Weissman
- Division of Epidemiology, New York State Psychiatric Institute, New York, NY, USA
- Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - J Wellmann
- Institute of Epidemiology and Social Medicine, University of Muenster, Münster, Germany
| | - G Willemsen
- Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - S H Witt
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - D F Levinson
- Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
| | - C M Lewis
- King's College London, MRC Social Genetic and Developmental Psychiatry Centre, London, UK
- King's College London, Department of Medical and Molecular Genetics, London, UK
| | - N R Wray
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
| | - J Flint
- Merton College, University of Oxford, Oxford, UK
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - P F Sullivan
- Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - K S Kendler
- Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
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Herta T, Fischer J, Berg T. Genetik metabolischer und viraler Lebererkrankungen. DER GASTROENTEROLOGE 2017; 12:16-31. [DOI: 10.1007/s11377-016-0128-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Mazor R, Addissie S, Jang Y, Tai CH, Rose J, Hakim F, Pastan I. Role of HLA-DP in the Presentation of Epitopes from the Truncated Bacterial PE38 Immunotoxin. AAPS J 2017; 19:117-129. [PMID: 27796910 PMCID: PMC7900900 DOI: 10.1208/s12248-016-9986-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 08/18/2016] [Indexed: 02/07/2023] Open
Abstract
Identification of helper T-cell epitopes is important in many fields of medicine. We previously used an experimental approach to identify T-cell epitopes in PE38, a truncated bacterial toxin used in immunotoxins. Here, we evaluated the ability of antibodies to DR, DP, or DQ to block T-cell responses to PE38 epitopes in 36 PBMC samples. We predicted the binding affinities of peptides to DR, DP, and DQ alleles using computational tools and analyzed their ability to predict the T-cell epitopes. We found that HLA-DR is responsible for 65% of the responses, DP 24%, and DQ 4%. One epitope that is presented in 20% of the samples (10/50) is entirely DP restricted and was not predicted to bind to DR or DP reference alleles using binding algorithms. We conclude that DP has an important role in helper T-cell response to PE38.
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Affiliation(s)
- Ronit Mazor
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Room 5106, Bethesda, Maryland, 20892-4264, USA
| | - Selamawit Addissie
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Room 5106, Bethesda, Maryland, 20892-4264, USA
| | - Youjin Jang
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Room 5106, Bethesda, Maryland, 20892-4264, USA
| | - Chin-Hsien Tai
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Room 5106, Bethesda, Maryland, 20892-4264, USA
| | - Jeremy Rose
- Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Fran Hakim
- Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Ira Pastan
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Room 5106, Bethesda, Maryland, 20892-4264, USA.
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Sakai A, Noguchi E, Fukushima T, Tagawa M, Iwabuchi A, Kita M, Kakisaka K, Miyasaka A, Takikawa Y, Sumazaki R. Identification of amino acids in antigen-binding site of class II HLA proteins independently associated with hepatitis B vaccine response. Vaccine 2016; 35:703-710. [PMID: 28043736 DOI: 10.1016/j.vaccine.2016.08.068] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Revised: 07/29/2016] [Accepted: 08/23/2016] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Genetic factors in class II human leukocyte antigen (HLA) have been reported to be associated with inter-individual variation in hepatitis B virus (HBV) vaccine response. However, the mechanism underlying the associations remains elusive. In particular, the broad linkage disequilibrium in HLA region complicates the localization of the independent effects of genetic variants. Thus, the present study aimed to identify the most probable causal variations in class II HLA loci involved in the immune response to HBV vaccine. METHODS We performed a case-control study to assess whether HLA-DRB1, -DQB1, and -DPB1 4-digit alleles were associated with the response to primary HBV vaccination in 574 healthy Japanese students. To identify causative variants, we next assessed independently associated amino acid variants in these loci using conditional logistic regression analysis. Furthermore, to clarify the functional effects of these variants on HLA proteins, we performed computational structural studies. RESULTS HLA-DRB1∗01:01, HLA-DRB1∗08:03, HLA-DQB1∗05:01, and HLA-DPB1∗04:02 were significantly associated with sufficient response, whereas HLA-DPB1∗05:01 was associated with poor response. We then identified amino acids independently associated with sufficient response, namely, leucine at position 26 of HLA-DRβ1 and glycine-glycine-proline-methionine at positions 84-87 of HLA-DPβ1. These amino acids were located in antigen-binding pocket 4 of HLA-DR and pocket 1 of HLA-DP, respectively, which are important structures for selective binding of antigenic peptides. In addition, the detected variations in HLA-DP protein were responsible for the differences in the electrostatic potentials of the pocket, which can explain in part the sufficient/poor vaccine responses. CONCLUSION HLA-DRβ1 position 26 and HLA-DPβ1 positions 84-87 are independently associated with anti-HBs production against HBV vaccine. Our results suggest that HBsAg presentation through these HLA pocket structures plays an important role in the inter-individual variability of HBV vaccination.
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Affiliation(s)
- Aiko Sakai
- Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
| | - Emiko Noguchi
- Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
| | - Takashi Fukushima
- Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
| | - Manabu Tagawa
- Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Atsushi Iwabuchi
- Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Masaki Kita
- Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Japan
| | - Keisuke Kakisaka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
| | - Akio Miyasaka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
| | - Yasuhiro Takikawa
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
| | - Ryo Sumazaki
- Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
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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.
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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.
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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.
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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
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Matsuura K, Isogawa M, Tanaka Y. Host genetic variants influencing the clinical course of hepatitis B virus infection. J Med Virol 2016; 88:371-379. [PMID: 26255971 DOI: 10.1002/jmv.24350] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [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.
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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
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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.
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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
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Association of human leukocyte antigen haplotypes with clearance and persistence of hepatitis B virus infection in northeastern China. Epidemiol Infect 2015; 143:2805-12. [PMID: 25592155 DOI: 10.1017/s0950268814003902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
This study investigated clinical implications of human leukocyte antigen (HLA) I and II haplotypes, in combination with HBV sub-genotype C2, in hepatitis B virus (HBV) infections in northeastern China. Here, HLA haplotypes of 230 HBV-infected patients were compared to 210 healthy, unrelated Han individuals. Of the 230 HBV-infected patients, 54 had acute self-limited hepatitis (ASH) with sub-genotype C2 (ASH-C2), 144 had chronic hepatitis (CH) with sub-genotypes C2 and B2 (CH-C2 and CH-B2), and 32 spontaneously recovered without sub-genotype results. All groups underwent HLA typing and haplotype analysis. The results revealed that A*02-DRB1*12 and A*02-B*15-DRB1*09 carriers were susceptible to HBV infection. A*02-B*15-DRB1*09 is probably associated with acute onset and viral clearance and A*02-DRB1*12, with viral persistence. In HBV infections, B*40-DRB1*12 was associated with HBV persistence, whereas B*46-DRB1*09, A*24-DRB1*14, and B*15-DRB1*04 carriers easily recovered from the disease. By contrast, when infected with the HBV-C2 sub-genotype, A*24-DRB1*14, B*15-DRB1*04, A*02-B*15, A*02-DRB1*15, and A*02-B*15-DRB1*09 carriers displayed an acute clinical course before recovery. This study reveals a relationship between HLA haplotypes and HBV pathogenesis, thereby providing potential therapeutic targets to treat HBV infection.
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Ollila H, Ravel JM, Han F, Faraco J, Lin L, Zheng X, Plazzi G, Dauvilliers Y, Pizza F, Hong SC, Jennum P, Knudsen S, Kornum B, Dong X, Yan H, Hong H, Coquillard C, Mahlios J, Jolanki O, Einen M, Arnulf I, Högl B, Frauscher B, Crowe C, Partinen M, Huang Y, Bourgin P, Vaarala O, Désautels A, Montplaisir J, Mack S, Mindrinos M, Fernandez-Vina M, Mignot E, Mignot E. HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy. Am J Hum Genet 2015; 96:136-46. [PMID: 25574827 DOI: 10.1016/j.ajhg.2014.12.010] [Citation(s) in RCA: 105] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 12/08/2014] [Indexed: 01/29/2023] Open
Abstract
Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1(∗)01:02-DQB1(∗)06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1(∗)01:03-DPB1(∗)04:02 (DP0402; odds ratio [OR] = 0.51 [0.38-0.67], p = 1.01 × 10(-6)) and HLA-DPA1(∗)01:03-DPB1(∗)04:01 (DP0401; OR = 0.61 [0.47-0.80], p = 2.07 × 10(-4)) and predisposing effects of HLA-DPB1(∗)05:01 in Asians (OR = 1.76 [1.34-2.31], p = 4.71 × 10(-05)). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 [0.38-0.55] p = 8.99 × 10(-17)) and DP0501 (OR = 1.38 [1.18-1.61], p = 7.11 × 10(-5)). HLA-class-II-independent associations with HLA-A(∗)11:01 (OR = 1.32 [1.13-1.54], p = 4.92 × 10(-4)), HLA-B(∗)35:03 (OR = 1.96 [1.41-2.70], p = 5.14 × 10(-5)), and HLA-B(∗)51:01 (OR = 1.49 [1.25-1.78], p = 1.09 × 10(-5)) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Emmanuel Mignot
- Stanford University Center for Sleep Sciences, Palo Alto, CA 94304, USA.
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