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Hitomi Y, Ueno K, Aiba Y, Nishida N, Kono M, Sugihara M, Kawai Y, Kawashima M, Khor SS, Sugi K, Kouno H, Kohno H, Naganuma A, Iwamoto S, Katsushima S, Furuta K, Nikami T, Mannami T, Yamashita T, Ario K, Komatsu T, Makita F, Shimada M, Hirashima N, Yokohama S, Nishimura H, Sugimoto R, Komura T, Ota H, Kojima M, Nakamuta M, Fujimori N, Yoshizawa K, Mano Y, Takahashi H, Hirooka K, Tsuruta S, Sato T, Yamasaki K, Kugiyama Y, Motoyoshi Y, Suehiro T, Saeki A, Matsumoto K, Nagaoka S, Abiru S, Yatsuhashi H, Ito M, Kawata K, Takaki A, Arai K, Arinaga-Hino T, Abe M, Harada M, Taniai M, Zeniya M, Ohira H, Shimoda S, Komori A, Tanaka A, Ishigaki K, Nagasaki M, Tokunaga K, Nakamura M. A genome-wide association study identified PTPN2 as a population-specific susceptibility gene locus for primary biliary cholangitis. Hepatology 2024; 80:776-790. [PMID: 38652555 DOI: 10.1097/hep.0000000000000894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 02/22/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND AND AIMS Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-nonspecific) and nonshared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC. APPROACH AND RESULTS Protein tyrosine phosphatase nonreceptor type 2 ( PTPN2) was identified as a novel PBC susceptibility gene locus through GWAS and subsequent genome-wide meta-analysis involving 2181 cases and 2699 controls from the Japanese population (GWAS-lead variant: rs8098858, p = 2.6 × 10 -8 ). In silico and in vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells and plasmacytoid dendritic cells. Infiltration of PTPN2-positive T-cells and plasmacytoid dendritic cells was confirmed in the portal area of the PBC liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758. CONCLUSIONS PTPN2 , a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC through an insufficient negative feedback loop caused by the risk allele of rs2292758 in IFN-γ signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment.
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Affiliation(s)
- Yuki Hitomi
- Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Kazuko Ueno
- Genome Medical Science Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yoshihiro Aiba
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Nao Nishida
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
- Department of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Michihiro Kono
- Laboratory for Human Immunogenetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Mitsuki Sugihara
- Division of Biomedical Information Analysis, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Yosuke Kawai
- Genome Medical Science Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | | | - Seik-Soon Khor
- Genome Medical Science Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
- Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore, Singapore
| | - Kazuhiro Sugi
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Hirotaka Kouno
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Hiroshi Kohno
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Atsushi Naganuma
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Satoru Iwamoto
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Shinji Katsushima
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Kiyoshi Furuta
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Toshiki Nikami
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Tomohiko Mannami
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Tsutomu Yamashita
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Keisuke Ario
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Tatsuji Komatsu
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Fujio Makita
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Masaaki Shimada
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Noboru Hirashima
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Shiro Yokohama
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Hideo Nishimura
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Rie Sugimoto
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Takuya Komura
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Hajime Ota
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Motoyuki Kojima
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Makoto Nakamuta
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Naoyuki Fujimori
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Kaname Yoshizawa
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Yutaka Mano
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Hironao Takahashi
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Kana Hirooka
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Satoru Tsuruta
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Takeaki Sato
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Kazumi Yamasaki
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Yuki Kugiyama
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | | | - Tomoyuki Suehiro
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Akira Saeki
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Kosuke Matsumoto
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Shinya Nagaoka
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Seigo Abiru
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | | | - Masahiro Ito
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Kazuhito Kawata
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Teruko Arinaga-Hino
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Japan
| | - Masaru Harada
- The Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Makiko Taniai
- Department of Medicine and Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Mikio Zeniya
- Department of Gastroenterology and Hepatology, Tokyo Jikei University School of Medicine, Tokyo, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University, Fukushima, Japan
| | - Shinji Shimoda
- Division of Gastroenterology and Hepatology, Third Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Atsumasa Komori
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Kazuyoshi Ishigaki
- Laboratory for Human Immunogenetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Masao Nagasaki
- Division of Biomedical Information Analysis, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
- Human Biosciences Unit for the Top Global Course Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan
| | - Katsushi Tokunaga
- Genome Medical Science Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Minoru Nakamura
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
- Division of Biomedical Information Analysis, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan
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Yu X, Chen Y, Chen J, Fan Y, Lu H, Wu D, Xu Y. Shared genetic architecture between autoimmune disorders and B-cell acute lymphoblastic leukemia: insights from large-scale genome-wide cross-trait analysis. BMC Med 2024; 22:161. [PMID: 38616254 PMCID: PMC11017616 DOI: 10.1186/s12916-024-03385-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 04/08/2024] [Indexed: 04/16/2024] Open
Abstract
BACKGROUND To study the shared genetic structure between autoimmune diseases and B-cell acute lymphoblastic leukemia (B-ALL) and identify the shared risk loci and genes and genetic mechanisms involved. METHODS Based on large-scale genome-wide association study (GWAS) summary-level data sets, we observed genetic overlaps between autoimmune diseases and B-ALL, and cross-trait pleiotropic analysis was performed to detect shared pleiotropic loci and genes. A series of functional annotation and tissue-specific analysis were performed to determine the influence of pleiotropic genes. The heritability enrichment analysis was used to detect crucial immune cells and tissues. Finally, bidirectional Mendelian randomization (MR) methods were utilized to investigate the casual associations. RESULTS Our research highlighted shared genetic mechanisms between seven autoimmune disorders and B-ALL. A total of 73 pleiotropic loci were identified at the genome-wide significance level (P < 5 × 10-8), 16 of which had strong evidence of colocalization. We demonstrated that several loci have been previously reported (e.g., 17q21) and discovered some novel loci (e.g., 10p12, 5p13). Further gene-level identified 194 unique pleiotropic genes, for example IKZF1, GATA3, IKZF3, GSDMB, and ORMDL3. Pathway analysis determined the key role of cellular response to cytokine stimulus, B cell activation, and JAK-STAT signaling pathways. SNP-level and gene-level tissue enrichment suggested that crucial role pleiotropic mechanisms involved in the spleen, whole blood, and EBV-transformed lymphocytes. Also, hyprcoloc and stratified LD score regression analyses revealed that B cells at different developmental stages may be involved in mechanisms shared between two different diseases. Finally, two-sample MR analysis determined causal effects of asthma and rheumatoid arthritis on B-ALL. CONCLUSIONS Our research proved shared genetic architecture between autoimmune disorders and B-ALL and shed light on the potential mechanism that might involve in.
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Affiliation(s)
- Xinghao Yu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Collaborative Innovation Center of Hematology, Institute of Blood and Marrow Transplantation, Soochow University, Suzhou, China
| | - Yiyin Chen
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Collaborative Innovation Center of Hematology, Institute of Blood and Marrow Transplantation, Soochow University, Suzhou, China
| | - Jia Chen
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yi Fan
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Huimin Lu
- Department of Outpatient and Emergency, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Depei Wu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
- Collaborative Innovation Center of Hematology, Institute of Blood and Marrow Transplantation, Soochow University, Suzhou, China.
| | - Yang Xu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
- Collaborative Innovation Center of Hematology, Institute of Blood and Marrow Transplantation, Soochow University, Suzhou, China.
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Fu Y, Kelly JA, Gopalakrishnan J, Pelikan RC, Tessneer KL, Pasula S, Grundahl K, Murphy DA, Gaffney PM. Massively parallel reporter assay confirms regulatory potential of hQTLs and reveals important variants in lupus and other autoimmune diseases. HGG ADVANCES 2024; 5:100279. [PMID: 38389303 PMCID: PMC10943488 DOI: 10.1016/j.xhgg.2024.100279] [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: 09/08/2023] [Revised: 02/15/2024] [Accepted: 02/18/2024] [Indexed: 02/24/2024] Open
Abstract
We designed a massively parallel reporter assay (MPRA) in an Epstein-Barr virus transformed B cell line to directly characterize the potential for histone post-translational modifications, i.e., histone quantitative trait loci (hQTLs), expression QTLs (eQTLs), and variants on systemic lupus erythematosus (SLE) and autoimmune (AI) disease risk haplotypes to modulate regulatory activity in an allele-dependent manner. Our study demonstrates that hQTLs, as a group, are more likely to modulate regulatory activity in an MPRA compared with other variant classes tested, including a set of eQTLs previously shown to interact with hQTLs and tested AI risk variants. In addition, we nominate 17 variants (including 11 previously unreported) as putative causal variants for SLE and another 14 for various other AI diseases, prioritizing these variants for future functional studies in primary and immortalized B cells. Thus, we uncover important insights into the mechanistic relationships among genotype, epigenetics, and gene expression in SLE and AI disease phenotypes.
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Affiliation(s)
- Yao Fu
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Jennifer A Kelly
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Jaanam Gopalakrishnan
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Neuro-Immune Regulome Unit, National Eye Institute, National Institute of Health, Bethesda, MD 20892, USA
| | - Richard C Pelikan
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Kandice L Tessneer
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Satish Pasula
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Kiely Grundahl
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - David A Murphy
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Patrick M Gaffney
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
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Wu Y, Qian Q, Liu Q, Wang R, Pu X, Li Y, Zhang H, You Z, Miao Q, Xiao X, Lian M, Wang Q, Nakamura M, Gershwin ME, Li Z, Ma X, Tang R. Osteoporosis and Primary Biliary Cholangitis: A Trans-ethnic Mendelian Randomization Analysis. Clin Rev Allergy Immunol 2024; 66:138-148. [PMID: 38554235 DOI: 10.1007/s12016-024-08986-4] [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] [Accepted: 03/08/2024] [Indexed: 04/01/2024]
Abstract
Osteoporosis is a major clinical problem in many autoimmune diseases, including primary biliary cholangitis (PBC), the most common autoimmune liver disease. Osteoporosis is a major cause of fracture and related mortality. However, it remains unclear whether PBC confers a causally risk-increasing effect on osteoporosis. Herein, we aimed to investigate the causal relationship between PBC and osteoporosis and whether the relationship is independent of potential confounders. We performed bidirectional Mendelian randomization (MR) analyses to investigate the association between PBC (8021 cases and 16,489 controls) and osteoporosis in Europeans (the UK Biobank and FinnGen Consortium: 12,787 cases and 726,996 controls). The direct effect of PBC on osteoporosis was estimated using multivariable MR analyses. An independent replication was conducted in East Asians (PBC: 2495 cases and 4283 controls; osteoporosis: 9794 cases and 168,932 controls). Trans-ethnic meta-analysis was performed by pooling the MR estimates of Europeans and East Asians. Inverse-variance weighted analyses revealed that genetic liability to PBC was associated with a higher risk of osteoporosis in Europeans (OR, 1.040; 95% CI, 1.016-1.064; P = 0.001). Furthermore, the causal effect of PBC on osteoporosis persisted after adjusting for BMI, calcium, lipidemic traits, and sex hormones. The causal relationship was further validated in the East Asians (OR, 1.059; 95% CI, 1.023-1.096; P = 0.001). Trans-ethnic meta-analysis confirmed that PBC conferred increased risk on osteoporosis (OR, 1.045; 95% CI, 1.025-1.067; P = 8.17 × 10-6). Our data supports a causal effect of PBC on osteoporosis, and the causality is independent of BMI, calcium, triglycerides, and several sex hormones.
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Affiliation(s)
- Yi Wu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Qiwei Qian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Qiaoyan Liu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Rui Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Xiting Pu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Yao Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Huayang Zhang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Zhengrui You
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Qi Miao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Xiao Xiao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Min Lian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Qixia Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Minoru Nakamura
- Department of Hepatology, Clinical Research Center, Nagasaki University Graduate School of Biomedical Sciences, NHO Nagasaki Medical Center, Kubara 2-1001-1, Omura City, Nagasaki, 856-8562, Japan
| | - M Eric Gershwin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Zhiqiang Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China.
- Qingdao University, Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao, China.
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.
- Institute of Aging & Tissue Regeneration, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai, 200001, China.
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Wiley MM, Khatri B, Joachims ML, Tessneer KL, Stolarczyk AM, Rasmussen A, Anaya JM, Aqrawi LA, Bae SC, Baecklund E, Björk A, Brun JG, Bucher SM, Dand N, Eloranta ML, Engelke F, Forsblad-d’Elia H, Fugmann C, Glenn SB, Gong C, Gottenberg JE, Hammenfors D, Imgenberg-Kreuz J, Jensen JL, Johnsen SJA, Jonsson MV, Kelly JA, Khanam S, Kim K, Kvarnström M, Mandl T, Martín J, Morris DL, Nocturne G, Norheim KB, Olsson P, Palm Ø, Pers JO, Rhodus NL, Sjöwall C, Skarstein K, Taylor KE, Tombleson P, Thorlacius GE, Venuturupalli S, Vital EM, Wallace DJ, Grundahl KM, Radfar L, Brennan MT, James JA, Scofield RH, Gaffney PM, Criswell LA, Jonsson R, Appel S, Eriksson P, Bowman SJ, Omdal R, Rönnblom L, Warner BM, Rischmueller M, Witte T, Farris AD, Mariette X, Shiboski CH, Wahren-Herlenius M, Alarcón-Riquelme ME, Ng WF, Sivils KL, Guthridge JM, Adrianto I, Vyse TJ, Tsao BP, Nordmark G, Lessard CJ. Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.05.561076. [PMID: 39071447 PMCID: PMC11275775 DOI: 10.1101/2023.10.05.561076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Fine mapping and bioinformatic analysis of the DDX6-CXCR5 genetic risk association in Sjögren's Disease (SjD) and Systemic Lupus Erythematosus (SLE) identified five common SNPs with functional evidence in immune cell types: rs4938573, rs57494551, rs4938572, rs4936443, rs7117261. Functional interrogation of nuclear protein binding affinity, enhancer/promoter regulatory activity, and chromatin-chromatin interactions in immune, salivary gland epithelial, and kidney epithelial cells revealed cell type-specific allelic effects for all five SNPs that expanded regulation beyond effects on DDX6 and CXCR5 expression. Mapping the local chromatin regulatory network revealed several additional genes of interest, including lnc-PHLDB1-1. Collectively, functional characterization implicated the risk alleles of these SNPs as modulators of promoter and/or enhancer activities that regulate cell type-specific expression of DDX6, CXCR5, and lnc-PHLDB1-1, among others. Further, these findings emphasize the importance of exploring the functional significance of SNPs in the context of complex chromatin architecture in disease-relevant cell types and tissues.
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Affiliation(s)
- Mandi M. Wiley
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
| | - Bhuwan Khatri
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
| | - Michelle L. Joachims
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
- Arthritis and Clinical Immunology Research Program, OMRF, Oklahoma City, Oklahoma, USA
| | - Kandice L. Tessneer
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
| | - Anna M. Stolarczyk
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
| | - Astrid Rasmussen
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
| | | | - Lara A. Aqrawi
- Department of Health Sciences, Kristiania University College, Oslo, Norway
- University of Oslo, Norway
| | | | | | | | - Johan G. Brun
- University of Bergen, Bergen, Norway
- Haukeland University Hospital, Bergen, Norway
| | | | - Nick Dand
- King’s College London, London, United Kingdom
| | | | | | | | | | - Stuart B. Glenn
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
| | - Chen Gong
- King’s College London, London, United Kingdom
| | | | | | | | | | | | | | - Jennifer A. Kelly
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
| | - Sharmily Khanam
- Arthritis and Clinical Immunology Research Program, OMRF, Oklahoma City, Oklahoma, USA
| | | | | | | | - Javier Martín
- Instituto de Biomedicina y Parasitología López-Neyra, Granada, Spain
| | | | - Gaetane Nocturne
- Université Paris-Saclay, Paris, France
- Assistance Publique – Hôpitaux de Paris, Hôpital Bicêtre, Paris, France
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Kiely M. Grundahl
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
- Arthritis and Clinical Immunology Research Program, OMRF, Oklahoma City, Oklahoma, USA
| | - Lida Radfar
- University of Oklahoma College of Dentistry, Oklahoma City, Oklahoma, USA
| | | | - Judith A. James
- Arthritis and Clinical Immunology Research Program, OMRF, Oklahoma City, Oklahoma, USA
- University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - R. Hal Scofield
- Arthritis and Clinical Immunology Research Program, OMRF, Oklahoma City, Oklahoma, USA
- University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
- US Department of Veteran Affairs Medical Center, Oklahoma City, Oklahoma, USA
| | - Patrick M. Gaffney
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
- University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Lindsey A. Criswell
- University of California San Francisco, San Francisco, California, USA
- National Human Genome Research Institute, NIH, Bethesda, Maryland, USA
| | | | | | | | - Simon J. Bowman
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Roald Omdal
- University of Bergen, Bergen, Norway
- Stavanger University Hospital, Stavanger, Norway
| | | | - Blake M. Warner
- National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA
| | | | | | - A. Darise Farris
- Arthritis and Clinical Immunology Research Program, OMRF, Oklahoma City, Oklahoma, USA
- University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Xavier Mariette
- Université Paris-Saclay, Paris, France
- Assistance Publique – Hôpitaux de Paris, Hôpital Bicêtre, Paris, France
| | | | | | | | - Marta E. Alarcón-Riquelme
- Karolinska Institutet, Solna, Sweden
- Genyo, Center for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Spain
| | | | - Wan-Fai Ng
- NIHR Newcastle Biomedical Research Centre and NIHR Newcastle Clinical Research Facility, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom
| | | | - Kathy L. Sivils
- Arthritis and Clinical Immunology Research Program, OMRF, Oklahoma City, Oklahoma, USA
| | - Joel M. Guthridge
- Arthritis and Clinical Immunology Research Program, OMRF, Oklahoma City, Oklahoma, USA
- University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Indra Adrianto
- Center for Bioinformatics, Department of Public Health Sciences, Henry Ford Health, Detroit, Michigan, USA
- Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, Michigan, USA
| | | | - Betty P. Tsao
- Medical University of South Carolina, Charleston, South Carolina, USA
| | | | - Christopher J. Lessard
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA
- University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
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6
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Fu Y, Kelly JA, Gopalakrishnan J, Pelikan RC, Tessneer KL, Pasula S, Grundahl K, Murphy DA, Gaffney PM. Massively Parallel Reporter Assay Confirms Regulatory Potential of hQTLs and Reveals Important Variants in Lupus and Other Autoimmune Diseases. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.17.553722. [PMID: 37645944 PMCID: PMC10462090 DOI: 10.1101/2023.08.17.553722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
Objective To systematically characterize the potential for histone post-translational modifications, i.e., histone quantitative trait loci (hQTLs), expression QTLs (eQTLs), and variants on systemic lupus erythematosus (SLE) and autoimmune (AI) disease risk haplotypes to modulate gene expression in an allele dependent manner. Methods We designed a massively parallel reporter assay (MPRA) containing ~32K variants and transfected it into an Epstein-Barr virus transformed B cell line generated from an SLE case. Results Our study expands our understanding of hQTLs, illustrating that epigenetic QTLs are more likely to contribute to functional mechanisms than eQTLs and other variant types, and a large proportion of hQTLs overlap transcription start sites (TSS) of noncoding RNAs. In addition, we nominate 17 variants (including 11 novel) as putative causal variants for SLE and another 14 for various other AI diseases, prioritizing these variants for future functional studies primary and immortalized B cells. Conclusion We uncover important insights into the mechanistic relationships between genotype, epigenetics, gene expression, and SLE and AI disease phenotypes.
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Affiliation(s)
- Yao Fu
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Jennifer A Kelly
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Jaanam Gopalakrishnan
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
- Neuro-Immune Regulome Unit, National Eye Institute, National Institute of Health, Bethesda, MD, 20892, USA
| | - Richard C Pelikan
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Kandice L Tessneer
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Satish Pasula
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Kiely Grundahl
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - David A Murphy
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
| | - Patrick M Gaffney
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA
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7
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Yang Y, He X, Rojas M, Leung PSC, Gao L. Mechanism-based target therapy in primary biliary cholangitis: opportunities before liver cirrhosis? Front Immunol 2023; 14:1184252. [PMID: 37325634 PMCID: PMC10266968 DOI: 10.3389/fimmu.2023.1184252] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 05/16/2023] [Indexed: 06/17/2023] Open
Abstract
Primary biliary cholangitis (PBC) is an immune-mediated liver disease characterized by cholestasis, biliary injuries, liver fibrosis, and chronic non-suppurative cholangitis. The pathogenesis of PBC is multifactorial and involves immune dysregulation, abnormal bile metabolism, and progressive fibrosis, ultimately leading to cirrhosis and liver failure. Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are currently used as first- and second-line treatments, respectively. However, many patients do not respond adequately to UDCA, and the long-term effects of these drugs are limited. Recent research has advanced our understanding the mechanisms of pathogenesis in PBC and greatly facilitated development of novel drugs to target mechanistic checkpoints. Animal studies and clinical trials of pipeline drugs have yielded promising results in slowing disease progression. Targeting immune mediated pathogenesis and anti-inflammatory therapies are focused on the early stage, while anti-cholestatic and anti-fibrotic therapies are emphasized in the late stage of disease, which is characterized by fibrosis and cirrhosis development. Nonetheless, it is worth noting that currently, there exists a dearth of therapeutic options that can effectively impede the progression of the disease to its terminal stages. Hence, there is an urgent need for further research aimed at investigating the underlying pathophysiology mechanisms with potential therapeutic effects. This review highlights our current knowledge of the underlying immunological and cellular mechanisms of pathogenesis in PBC. Further, we also address current mechanism-based target therapies for PBC and potential therapeutic strategies to improve the efficacy of existing treatments.
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Affiliation(s)
- Yushu Yang
- Department of Rheumatology and Immunology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - XiaoSong He
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, Davis, CA, United States
| | - Manuel Rojas
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, Davis, CA, United States
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia
| | - Patrick S. C. Leung
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, Davis, CA, United States
| | - Lixia Gao
- Department of Rheumatology and Immunology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, Davis, CA, United States
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Abstract
BACKGROUND Autoimmune hepatitis has an unknown cause and genetic associations that are not disease-specific or always present. Clarification of its missing causality and heritability could improve prevention and management strategies. AIMS Describe the key epigenetic and genetic mechanisms that could account for missing causality and heritability in autoimmune hepatitis; indicate the prospects of these mechanisms as pivotal factors; and encourage investigations of their pathogenic role and therapeutic potential. METHODS English abstracts were identified in PubMed using multiple key search phases. Several hundred abstracts and 210 full-length articles were reviewed. RESULTS Environmental induction of epigenetic changes is the prime candidate for explaining the missing causality of autoimmune hepatitis. Environmental factors (diet, toxic exposures) can alter chromatin structure and the production of micro-ribonucleic acids that affect gene expression. Epistatic interaction between unsuspected genes is the prime candidate for explaining the missing heritability. The non-additive, interactive effects of multiple genes could enhance their impact on the propensity and phenotype of autoimmune hepatitis. Transgenerational inheritance of acquired epigenetic marks constitutes another mechanism of transmitting parental adaptations that could affect susceptibility. Management strategies could range from lifestyle adjustments and nutritional supplements to precision editing of the epigenetic landscape. CONCLUSIONS Autoimmune hepatitis has a missing causality that might be explained by epigenetic changes induced by environmental factors and a missing heritability that might reflect epistatic gene interactions or transgenerational transmission of acquired epigenetic marks. These unassessed or under-evaluated areas warrant investigation.
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
- Professor Emeritus of Medicine, Mayo Clinic College of Medicine and Science, 200 First Street SW, Rochester, MN, 55905, USA.
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Li H, Ye M, Hu Z, Lu H, Zheng D, Wu M, Ge T, Xu S, Ge Z, Zhang S, Xu G, Chen H. IKZF3 is a novel prognostic biomarker for head and neck squamous cell carcinoma: A study based on bioinformatics analysis. Medicine (Baltimore) 2023; 102:e33124. [PMID: 36930079 PMCID: PMC10019242 DOI: 10.1097/md.0000000000033124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 02/08/2023] [Indexed: 03/18/2023] Open
Abstract
In the past few years, immunotherapy of tumors has become an extensive research hotspot, and the value of IKZF family genes in the tumor microenvironment has also been increasingly recognized. However, the expression of the IKAROS family zinc finger 3 (IKZF3) gene in human head and neck squamous cell carcinoma (HNSCC) and its prognostic value were not reported for the main subset until now. In the present study, we analyzed the relationship between IKZF3 gene expression and the survival of HNSCC patients. To evaluate the potential of IKZF3 as a prognostic biomarker for HNSCC comprehensively, multiple online analysis tools, including UALCAN, cBioPortal, GEPIA, WebGestalt, String, Genomic Data Commons, and TIMER databases were utilized in our study. We observed that the HNSCC patients with higher IKZF3 expression tended to exhibit longer overall survival. Univariate and multivariate Cox regression analyses indicated that age and grade were independent prognostic indicators in HNSCC. Moreover, Gene Ontology and KEGG function enrichment analyses showed that several pathways in HNSCC might be pivotal pathways regulated by IKZF3, which revealed that IKZF3 was probably participating in the occurrence and development of HNSCC. Furthermore, the hypomethylation of the IKZF3 gene was closely associated with genes that observed mutation in HNSCC. IKZF3 was significantly correlated with several immune cells in HNSCC (e.g., CD8+ T cell, CD4+ cell, and dendritic cell). We explored the potential prognostic values and roles of the IKZF3 in HNSCC, revealing that IKZF3 was probably a novel and reliable prognostic biomarker for patients with HNSCC.
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Affiliation(s)
- Hongxiang Li
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
- School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Mengmeng Ye
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
- School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Zeyang Hu
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
- School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Haoxuan Lu
- Department of Cardiology, The Affiliated Hospital of Medical School, Ningbo University, Ningbo, Zhejiang, China
| | - Dawei Zheng
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Mi Wu
- Department of Emergency, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Ting Ge
- Department of Respiratory, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Shuguang Xu
- Department of Respiratory, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Zhen Ge
- Department of Cardiology, The Affiliated Hospital of Medical School, Ningbo University, Ningbo, Zhejiang, China
| | - Shuoni Zhang
- Department of Emergency, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Guodong Xu
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Hang Chen
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
- School of Medicine, Ningbo University, Ningbo, Zhejiang, China
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10
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Hitomi Y, Nakamura M. The Genetics of Primary Biliary Cholangitis: A GWAS and Post-GWAS Update. Genes (Basel) 2023; 14:405. [PMID: 36833332 PMCID: PMC9957238 DOI: 10.3390/genes14020405] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/27/2023] [Accepted: 02/01/2023] [Indexed: 02/09/2023] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic, progressive cholestatic liver disease in which the small intrahepatic bile ducts are destroyed by autoimmune reactions. Among autoimmune diseases, which are polygenic complex traits caused by the combined contribution of genetic and environmental factors, PBC exhibits the strongest involvement of genetic heritability in disease development. As at December 2022, genome-wide association studies (GWASs) and associated meta-analyses identified approximately 70 PBC susceptibility gene loci in various populations, including those of European and East Asian descent. However, the molecular mechanisms through which these susceptibility loci affect the pathogenesis of PBC are not fully understood. This study provides an overview of current data regarding the genetic factors of PBC as well as post-GWAS approaches to identifying primary functional variants and effector genes in disease-susceptibility loci. Possible mechanisms of these genetic factors in the development of PBC are also discussed, focusing on four major disease pathways identified by in silico gene set analyses, namely, (1) antigen presentation by human leukocyte antigens, (2) interleukin-12-related pathways, (3) cellular responses to tumor necrosis factor, and (4) B cell activation, maturation, and differentiation pathways.
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Affiliation(s)
- Yuki Hitomi
- Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Minoru Nakamura
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, 2-1001-1 Kubara, Omura 856-8562, Japan
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 2-1001-1 Kubara, Omura 856-8562, Japan
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, 2-1001-1 Kubara, Omura 856-8562, Japan
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11
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Mohsen RT, Al-Azzawi RH, Ad’hiah AH. A single-nucleotide polymorphism of IL12A gene (rs582537 A/C/G) and susceptibility to chronic hepatitis B virus infection among Iraqi patients. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2022. [DOI: 10.1186/s43042-022-00322-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
AbstractA case–control study (80 patients with chronic hepatitis B virus [HBV] infection and 96 controls) was performed to evaluate the association of an IL12A gene variant (rs582537 A/C/G) with HBV infection. Allele G showed a significantly lower frequency in patients compared to controls (31.2 vs. 46.9%; probability [p] = 0.009; corrected p [pc] = 0.027) and was associated with a lower risk of HBV infection (odds ratio [OR] = 0.49; 95% confidence interval [CI] = 0.29–0.83). A similar lower risk was associated with genotypes CG (17.5 vs. 29.2; OR = 0.25; 95% CI = 0.08–0.81; p = 0.02) and GG (10.0 vs. 16.7; OR = 0.25; 95% CI = 0.07–0.91; p = 0.036), but the pc value was not significant (0.12 and 0.126, respectively). Serum IL-35 levels showed significant differences between individuals of different genotypes (p = 0.007). The highest median was associated with CA genotype (286.5 pg/mL), followed by genotypes CG (227.0 pg/mL), GG (206.5 pg/mL), CC (169.0 pg/mL), AA (137.5 pg/mL) and finally AG (125.0 pg/mL). In conclusion, rs582537 appears to be an important genetic variant that may influence not only susceptibility to HBV infection but IL-35 levels.
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12
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Abstract
Primary biliary cholangitis (PBC) is a rare disease of the liver characterized by an autoimmune attack on the small bile ducts. PBC is a complex trait, meaning that a large list of genetic factors interacts with environmental agents to determine its onset. Genome-wide association studies have had a huge impact in fostering research in PBC, but many steps need still to be done compared with other autoimmune diseases of similar prevalence. This review presents the state-of-the-art regarding the genetic architecture of PBC and provides some thoughtful reflections about possible future lines of research, which can be helpful to fill the missing heritability gap in PBC.
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Affiliation(s)
- Alessio Gerussi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900 Monza (MB), Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy.
| | - Rosanna Asselta
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele 20072, Italy; Humanitas Clinical and Research Center, IRCCS, Via Manzoni 56, Rozzano 20089, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900 Monza (MB), Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy.
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13
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Chen R, Tang R, Ma X, Gershwin ME. Immunologic Responses and the Pathophysiology of Primary Biliary Cholangitis. Clin Liver Dis 2022; 26:583-611. [PMID: 36270718 DOI: 10.1016/j.cld.2022.06.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease with a female predisposition and selective destruction of intrahepatic small bile ducts leading to nonsuppurative destructive cholangitis. It is characterized by seropositivity of antimitochondrial antibodies or PBC-specific antinuclear antibodies, progressive cholestasis, and typical liver histologic manifestations. Destruction of the protective bicarbonate-rich umbrella is attributed to the decreased expression of membrane transporters in biliary epithelial cells (BECs), leading to the accumulation of hydrophobic bile acids and sensitizing BECs to apoptosis. A recent X-wide association study reveals a novel risk locus on the X chromosome, which reiterates the importance of Treg cells.
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Affiliation(s)
- Ruiling Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China.
| | - M Eric Gershwin
- Division of Rheumatology-Allergy and Clinical Immunology, University of California at Davis, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616, USA.
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14
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Abstract
Primary biliary cholangitis (PBC) is a cholestatic liver disease with potential evolution to liver cirrhosis when left untreated. Despite being rare, PBC has a substantial impact on the quality of life and survival of affected patients. Women are the most diagnosed worldwide; however, male subjects seem to have more aggressive disease and worse prognosis. Changing epidemiologic trends are emerging in PBC, with increasing global prevalence and slight smoothing of sex differences. In this review we present available data on incidence rates and prevalence of PBC worldwide, highlighting geographic differences and factors impacting clinical outcomes.
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Affiliation(s)
- Francesca Colapietro
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via A. Manzoni 56, Rozzano 20089, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Arianna Bertazzoni
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via A. Manzoni 56, Rozzano 20089, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Ana Lleo
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via A. Manzoni 56, Rozzano 20089, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
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15
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Mulinacci G, Palermo A, Gerussi A, Asselta R, Gershwin ME, Invernizzi P. New insights on the role of human leukocyte antigen complex in primary biliary cholangitis. Front Immunol 2022; 13:975115. [PMID: 36119102 PMCID: PMC9471323 DOI: 10.3389/fimmu.2022.975115] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/11/2022] [Indexed: 01/04/2023] Open
Abstract
Primary Biliary Cholangitis (PBC) is a rare autoimmune cholangiopathy. Genetic studies have shown that the strongest statistical association with PBC has been mapped in the human leukocyte antigen (HLA) locus, a highly polymorphic area that mostly contribute to the genetic variance of the disease. Furthermore, PBC presents high variability throughout different population groups, which may explain the different geoepidemiology of the disease. A major role in defining HLA genetic contribution has been given by genome-wide association studies (GWAS) studies; more recently, new technologies have been developed to allow a deeper understanding. The study of the altered peptides transcribed by genetic alterations also allowed the development of novel therapeutic strategies in the context of immunotolerance. This review summarizes what is known about the immunogenetics of PBC with a focus on the HLA locus, the different distribution of HLA alleles worldwide, and how HLA modifications are associated with the pathogenesis of PBC. Novel therapeutic strategies are also outlined.
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Affiliation(s)
- Giacomo Mulinacci
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Andrea Palermo
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Alessio Gerussi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Rosanna Asselta
- Department of Biomedical Sciences, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Merrill Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA, United States
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. HLA, gut microbiome and hepatic autoimmunity. Front Immunol 2022; 13:980768. [PMID: 36059527 PMCID: PMC9433828 DOI: 10.3389/fimmu.2022.980768] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 07/25/2022] [Indexed: 12/12/2022] Open
Abstract
Genetic susceptibility to autoimmune liver diseases is conferred mainly by polymorphisms of genes encoding for the human leukocyte antigens (HLA). The strongest predisposition to autoimmune hepatitis type 1 (AIH-1) is linked to the allele DRB1*03:01, possession of which is associated with earlier disease onset and more severe course. In populations where this allele is very rare, such as in Asia, and in DRB1*03-negative patients, risk of AIH-1 is conferred by DRB1*04, which is associated with later disease onset and milder phenotype. AIH type 2 (AIH-2) is associated with DRB1*07. The pediatric condition referred to as autoimmune sclerosing cholangitis (ASC), is associated with the DRB1*13 in populations of Northern European ancestry. DRB1*1501 is protective from AIH-1, AIH-2 and ASC in Northern European populations. Possession of the DRB1*08 allele is associated with an increased risk of primary biliary cholangitis (PBC) across different populations. DRB1*03:01 and B*08:01 confer susceptibility to primary sclerosing cholangitis (PSC), as well as DRB1*13 and DRB1*15 in Europe. The hepatic blood supply is largely derived from the splanchnic circulation, suggesting a pathophysiological role of the gut microbiome. AIH appears to be associated with dysbiosis, increased gut permeability, and translocation of intestinal microbial products into the circulation; molecular mimicry between microbial and host antigens may trigger an autoaggressive response in genetically-predisposed individuals. In PBC an altered enteric microbiome may affect intestinal motility, immunological function and bile secretion. Patients with PSC have a gut microbial profile different from health as well as from patients with inflammatory bowel disease without PSC.
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Affiliation(s)
- Benedetta Terziroli Beretta-Piccoli
- Faculty of Biomedical Sciences, Epatocentro Ticino and Università della Svizzera Italiana, Lugano, Switzerland
- MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
- *Correspondence: Benedetta Terziroli Beretta-Piccoli,
| | - Giorgina Mieli-Vergani
- MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
| | - Diego Vergani
- MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
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The latest research trends in primary biliary cholangitis: a bibliometric analysis. Clin Exp Med 2022; 23:347-355. [PMID: 35389157 DOI: 10.1007/s10238-022-00825-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 03/19/2022] [Indexed: 01/03/2023]
Abstract
The bibliometric analysis uses the citation count of an article to measure its impact in the scientific community, but no study has been undertaken to determine the most influential papers in the field of primary biliary cholangitis (PBC). This study aimed to investigate the global research interest regarding PBC in dentistry using a bibliometric approach. We searched the Web of Science Core Collection database to find the top 100 most cited (T100) articles focusing on PBC. The information about each article including citations, authors, journals, countries, institutions, and keywords was recorded for bibliometric analysis. The T100 articles related to PBC were published from 1983 to 2019 and were originated from 26 countries. A total of 805 different authors were from 342 different institutions, and articles written by them were published in 35 journals. The five most frequently occurring keywords were "biochemical response," "ursodeoxycholic acid," "primary biliary cirrhosis," "antimitochondrial antibody," and "autoimmunity." The T100 articles were classified into different research focuses: pathogenesis (41%), treatment (20%), prognosis (12%), epidemiology (9%), diagnosis (8%), and others (10%). These 100 articles included 32 observational studies, 29 basic research articles, 15 reviews, eight meta-analyses, 12 clinical trials, and four clinical guidelines. The 100 top-cited articles are marked with the leading countries, institutions, journals, hotspots, and development trends in the PBC field that could provide the foundation for further investigations.
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18
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Matsumoto K, Ohfuji S, Abe M, Komori A, Takahashi A, Fujii H, Kawata K, Noritake H, Tadokoro T, Honda A, Asami M, Namisaki T, Ueno M, Sato K, Kakisaka K, Arakawa M, Ito T, Tanaka K, Matsui T, Setsu T, Takamura M, Yasuda S, Katsumi T, Itakura J, Sano T, Tamura Y, Miura R, Arizumi T, Asaoka Y, Uno K, Nishitani A, Ueno Y, Terai S, Takikawa Y, Morimoto Y, Yoshiji H, Mochida S, Ikegami T, Masaki T, Kawada N, Ohira H, Tanaka A. Environmental factors, medical and family history, and comorbidities associated with primary biliary cholangitis in Japan: a multicenter case-control study. J Gastroenterol 2022; 57:19-29. [PMID: 34796398 DOI: 10.1007/s00535-021-01836-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 11/04/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is considered to be caused by the interaction between genetic background and environmental triggers. Previous case-control studies have indicated the associations of environmental factors (tobacco smoking, a history of urinary tract infection, and hair dye) use with PBC. Therefore, we conducted a multicenter case-control study to identify the environmental factors associated with the development of PBC in Japan. METHODS From 21 participating centers in Japan, we prospectively enrolled 548 patients with PBC (male/female = 78/470, median age 66), and 548 age- and sex-matched controls. These participants completed a questionnaire comprising 121 items with respect to demographic, anthropometric, socioeconomic features, lifestyle, medical/familial history, and reproductive history in female individuals. The association was determined using conditional multivariate logistic regression analysis. RESULTS The identified factors were vault toilet at home in childhood [odds ratio (OR), 1.63; 95% confidence interval (CI), 1.01-2.62], unpaved roads around the house in childhood (OR, 1.43; 95% CI, 1.07-1.92), ever smoking (OR, 1.70; 95% CI, 1.28-2.25), and hair dye use (OR, 1.57; 95% CI, 1.15-2.14) in the model for lifestyle factors, and a history of any type of autoimmune disease (OR, 8.74; 95% CI, 3.99-19.13), a history of Cesarean section (OR, 0.20; 95% CI, 0.077-0.53), and presence of PBC in first-degree relatives (OR, 21.1; 95% CI, 6.52-68.0) in the model for medical and familial factors. CONCLUSIONS These results suggest that poor environmental hygiene in childhood (vault toilets and unpaved roads) and chronic exposure to chemicals (smoking and hair dye use) are likely to be risk factors for the development of PBC in Japan.
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Affiliation(s)
- Kosuke Matsumoto
- Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, Japan.
| | - Satoko Ohfuji
- Department of Public Health, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Atsumasa Komori
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Nagasaki, Japan
| | - Atsushi Takahashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hideki Fujii
- Department of Premier Preventive Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Kazuhito Kawata
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Hidenao Noritake
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa, Japan
| | - Akira Honda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Maiko Asami
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Tadashi Namisaki
- Department of Gastroenterology, Nara Medical University, Nara, Japan
| | - Masayuki Ueno
- Department of Gastroenterology and Hepatology, Kurashiki Central Hospital, Okayama, Japan
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ken Sato
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Keisuke Kakisaka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
| | - Mie Arakawa
- Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan
| | - Takanori Ito
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Kazunari Tanaka
- Center for Gastroenterology, Teine-Keijinkai Hospital, Hokkaido, Japan
| | - Takeshi Matsui
- Center for Gastroenterology, Teine-Keijinkai Hospital, Hokkaido, Japan
| | - Toru Setsu
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Masaaki Takamura
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Gifu, Japan
| | - Tomohiro Katsumi
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Tomoya Sano
- Division of Gastroenterology, Department of Internal Medicine, Kurume University School of Medicine, Fukuoka, Japan
| | - Yamato Tamura
- Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, Japan
| | - Ryo Miura
- Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, Japan
| | - Toshihiko Arizumi
- Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, Japan
| | - Yoshinari Asaoka
- Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, Japan
| | - Kiyoko Uno
- Teikyo Academic Research Center, Teikyo University, Tokyo, Japan
| | - Ai Nishitani
- Teikyo Academic Research Center, Teikyo University, Tokyo, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yasuhiro Takikawa
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
| | - Youichi Morimoto
- Department of Gastroenterology and Hepatology, Kurashiki Central Hospital, Okayama, Japan
| | - Hitoshi Yoshiji
- Department of Gastroenterology, Nara Medical University, Nara, Japan
| | - Satoshi Mochida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Tadashi Ikegami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, Japan
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Xiang B, Deng C, Qiu F, Li J, Li S, Zhang H, Lin X, Huang Y, Zhou Y, Su J, Lu M, Ma Y. Single cell sequencing analysis identifies genetics-modulated ORMDL3 + cholangiocytes having higher metabolic effects on primary biliary cholangitis. J Nanobiotechnology 2021; 19:406. [PMID: 34872583 PMCID: PMC8647381 DOI: 10.1186/s12951-021-01154-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 11/21/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is a classical autoimmune disease, which is highly influenced by genetic determinants. Many genome-wide association studies (GWAS) have reported that numerous genetic loci were significantly associated with PBC susceptibility. However, the effects of genetic determinants on liver cells and its immune microenvironment for PBC remain unclear. RESULTS We constructed a powerful computational framework to integrate GWAS summary statistics with scRNA-seq data to uncover genetics-modulated liver cell subpopulations for PBC. Based on our multi-omics integrative analysis, 29 risk genes including ORMDL3, GSNK2B, and DDAH2 were significantly associated with PBC susceptibility. By combining GWAS summary statistics with scRNA-seq data, we found that cholangiocytes exhibited a notable enrichment by PBC-related genetic association signals (Permuted P < 0.05). The risk gene of ORMDL3 showed the highest expression proportion in cholangiocytes than other liver cells (22.38%). The ORMDL3+ cholangiocytes have prominently higher metabolism activity score than ORMDL3- cholangiocytes (P = 1.38 × 10-15). Compared with ORMDL3- cholangiocytes, there were 77 significantly differentially expressed genes among ORMDL3+ cholangiocytes (FDR < 0.05), and these significant genes were associated with autoimmune diseases-related functional terms or pathways. The ORMDL3+ cholangiocytes exhibited relatively high communications with macrophage and monocyte. Compared with ORMDL3- cholangiocytes, the VEGF signaling pathway is specific for ORMDL3+ cholangiocytes to interact with other cell populations. CONCLUSIONS To the best of our knowledge, this is the first study to integrate genetic information with single cell sequencing data for parsing genetics-influenced liver cells for PBC risk. We identified that ORMDL3+ cholangiocytes with higher metabolism activity play important immune-modulatory roles in the etiology of PBC.
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Affiliation(s)
- Bingyu Xiang
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Chunyu Deng
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150080, China
| | - Fei Qiu
- Institute of Biomedical Big Data, School of Ophthalmology and Optometry and Eye Hospital, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Jingjing Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China
| | - Shanshan Li
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Huifang Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Xiuli Lin
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Yukuan Huang
- Institute of Biomedical Big Data, School of Ophthalmology and Optometry and Eye Hospital, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Yijun Zhou
- Institute of Biomedical Big Data, School of Ophthalmology and Optometry and Eye Hospital, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Jianzhong Su
- Institute of Biomedical Big Data, School of Ophthalmology and Optometry and Eye Hospital, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325011, Zhejiang, China
| | - Mingqin Lu
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
| | - Yunlong Ma
- Institute of Biomedical Big Data, School of Ophthalmology and Optometry and Eye Hospital, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China.
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rs9459874 and rs1012656 in CCR6/FGFR1OP confer susceptibility to primary biliary cholangitis. J Autoimmun 2021; 126:102775. [PMID: 34864633 DOI: 10.1016/j.jaut.2021.102775] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 11/23/2021] [Indexed: 12/18/2022]
Abstract
Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease that appears to be strongly influenced by genetic factors. Recently, an international meta-analysis of genome-wide association studies (GWAS) identified CC-Motif Chemokine Receptor-6 (CCR6) and FGFR1 Oncogene-Partner (FGFR1OP) as PBC-susceptibility genes. However, the lead single nucleotide polymorphisms (SNPs) of CCR6/FGFR1OP showed low linkage disequilibrium with each other in East Asian and European populations. Additionally, the primary functional variants and the molecular mechanisms responsible for PBC-susceptibility remain unclear. Here, among the PBC-susceptibility SNPs identified by high-density association mapping in our previous meta-GWAS (Patients: n = 10,516; healthy controls: n = 20,772) within the CCR6/FGFR1OP locus, rs9459874 and rs1012656 were identified as primary functional variants. These functional variants accounted for the effects of GWAS-identified lead SNPs in CCR6/FGFR1OP. Additionally, the roles of rs9459874 and rs1012656 in regulating FGFR1OP transcription and CCR6 translation, respectively, were supported by expression quantitative trait loci (eQTL) analysis and gene editing technology using the CRISPR/Cas9 system. Immunohistochemistry showed higher expression of CCR6 protein in the livers of patients with PBC than in those of a non-diseased control. In conclusion, we identified primary functional variants in CCR6/FGFR1OP and revealed the molecular mechanisms by which these variants confer PBC-susceptibility in an eQTL-dependent or -independent manner. The approach in this study is applicable for the elucidation of the pathogenesis of other autoimmune disorders in which CCR6/FGFR1OP is known as a susceptibility locus, as well as PBC.
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21
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Regional heritability mapping identifies several novel loci (STAT4, ULK4, and KCNH5) for primary biliary cholangitis in the Japanese population. Eur J Hum Genet 2021; 29:1282-1291. [PMID: 33833419 PMCID: PMC8385030 DOI: 10.1038/s41431-021-00854-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 01/22/2021] [Accepted: 02/23/2021] [Indexed: 02/02/2023] Open
Abstract
While the advent of GWAS more than a decade ago has ushered in remarkable advances in our understanding of complex traits, the limitations of single-SNP analysis have also led to the development of several other approaches. Simulation studies have shown that the regional heritability mapping (RHM) method, which makes use of multiple adjacent SNPs jointly to estimate the genetic effect of a given region of the genome, generally has higher detection power than single-SNP GWAS. However, thus far its use has been mostly limited to agricultural settings, and its potential for the discovery of new genes in human diseases is yet to be fully exploited. In this study, by applying the RHM method to primary biliary cholangitis (PBC) in the Japanese population, we identified three novel loci (STAT4, ULK4, and KCNH5) at the genome-wide significance level, two of which (ULK4 and KCNH5) have not been found associated with PBC in any population previously. Notably, these genes could not be detected by using conventional single-SNP GWAS, highlighting the potential of the RHM method for the detection of new susceptibility loci in human diseases. These findings thereby provide strong empirical evidence that RHM is an effective and practical complementary approach to GWAS in this context. Also, liver tissue mRNA microarray analysis revealed higher gene expression levels in ULK4 in PBC patients (P < 0.01). Lastly, we estimated the common SNP heritability of PBC in the Japanese population (0.210 ± 0.026).
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22
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The genetic architecture of primary biliary cholangitis. Eur J Med Genet 2021; 64:104292. [PMID: 34303876 DOI: 10.1016/j.ejmg.2021.104292] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 07/03/2021] [Accepted: 07/21/2021] [Indexed: 12/12/2022]
Abstract
Primary biliary cholangitis (PBC) is a rare autoimmune disease of the liver affecting the small bile ducts. From a genetic point of view, PBC is a complex trait and several genetic and environmental factors have been called in action to explain its etiopathogenesis. Similarly to other complex traits, PBC has benefited from the introduction of genome-wide association studies (GWAS), which identified many variants predisposing or protecting toward the development of the disease. While a progressive endeavour toward the characterization of candidate loci and downstream pathways is currently ongoing, there is still a relatively large portion of heritability of PBC to be revealed. In addition, genetic variation behind progression of the disease and therapeutic response are mostly to be investigated yet. This review outlines the state-of-the-art regarding the genetic architecture of PBC and provides some hints for future investigations, focusing on the study of gene-gene interactions, the application of whole-genome sequencing techniques, and the investigation of X chromosome that can be helpful to cover the missing heritability gap in PBC.
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23
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Asselta R, Paraboschi EM, Gerussi A, Cordell HJ, Mells GF, Sandford RN, Jones DE, Nakamura M, Ueno K, Hitomi Y, Kawashima M, Nishida N, Tokunaga K, Nagasaki M, Tanaka A, Tang R, Li Z, Shi Y, Liu X, Xiong M, Hirschfield G, Siminovitch KA, Carbone M, Cardamone G, Duga S, Gershwin ME, Seldin MF, Invernizzi P. X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis. Gastroenterology 2021; 160:2483-2495.e26. [PMID: 33675743 PMCID: PMC8169555 DOI: 10.1053/j.gastro.2021.02.061] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 02/15/2021] [Accepted: 02/25/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. METHODS We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). RESULTS Single-marker association analyses found approximately 100 loci displaying P < 5 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10-6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10-9; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). CONCLUSIONS This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.
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Affiliation(s)
- Rosanna Asselta
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; IRCCS Humanitas Research Hospital, Milan, Italy
| | - Elvezia M Paraboschi
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; IRCCS Humanitas Research Hospital, Milan, Italy
| | - Alessio Gerussi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases, San Gerardo Hospital, Monza, Italy
| | - Heather J Cordell
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, United Kingdom
| | - George F Mells
- Academic Department of Medical Genetics, Cambridge University, Cambridge, United Kingdom
| | - Richard N Sandford
- Academic Department of Medical Genetics, Cambridge University, Cambridge, United Kingdom
| | - David E Jones
- Faculty of Medical Sciences, Newcastle University, Newcastle, United Kingdom
| | - Minoru Nakamura
- Clinical Research Center, National Hospital Organization, Nagasaki Medical Center, Nagasaki, Japan; Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Nagasaki, Japan
| | - Kazuko Ueno
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yuki Hitomi
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Minae Kawashima
- 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
| | - Katsushi Tokunaga
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan; Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masao Nagasaki
- Human Biosciences Unit for the Top Global Course Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan; Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Zhiqiang Li
- Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, China; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China
| | - Yongyong Shi
- Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, China; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China
| | - Xiangdong Liu
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, Nanjing, Jiangsu, China
| | - Ma Xiong
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Gideon Hirschfield
- Toronto General Hospital Research Institute, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Katherine A Siminovitch
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Mount Sinai Hospital, Lunenfeld Tanenbaum Research Institute and Toronto General Research Institute, Toronto, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Marco Carbone
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases, San Gerardo Hospital, Monza, Italy
| | - Giulia Cardamone
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; IRCCS Humanitas Research Hospital, Milan, Italy
| | - Stefano Duga
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; IRCCS Humanitas Research Hospital, Milan, Italy
| | | | | | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases, San Gerardo Hospital, Monza, Italy.
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24
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Punia S, Juran BD, Ali AH, Schlicht EM, Moore RM, Sun Z, Lazaridis KN. Evaluation of circulating cell-free DNA in cholestatic liver disease using liver-specific methylation markers. BMC Gastroenterol 2021; 21:149. [PMID: 33794792 PMCID: PMC8017778 DOI: 10.1186/s12876-021-01741-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 03/25/2021] [Indexed: 11/10/2022] Open
Abstract
Background Quantification of circulating organ-specific cell-free DNA (cfDNA) provides a sensitive measure of ongoing cell death that could benefit evaluation of the cholestatic liver diseases primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), which lack reliable non-invasive biomarkers. Our goal in this pilot study was to determine whether liver-specific cfDNA levels are increased in PBC and PSC patients relative to controls and in advanced versus early disease, to evaluate their potential as novel disease biomarkers. Methods Peripheral blood derived bisulfite-treated DNA was PCR amplified from patients with PBC (n = 48), PSC (n = 48) and controls (n = 96) to evaluate methylation status at 16 CpG sites reported to be specifically unmethylated in liver tissue near the genes IGF2R, ITIH4 and VTN. Amplicons were used to prepare paired end libraries which were sequenced on a MiSeq sequencer. Trimmed reads were aligned and used to determine unmethylation ratios and to calculate concentration of liver-specific cfDNA. Comparisons between groups were performed using the two-tailed Mann–Whitney Test and relationships between variables were evaluated using Pearson’s Correlation. Results Levels of liver-specific cfDNA, as measured at the 3 genetic loci, were increased in PBC and PSC patients relative to controls and in late-stage relative to early-stage patients. As well, cfDNA levels were correlated with levels of alkaline phosphatase, a commonly used biochemical test to evaluate disease severity in liver disease, in patients, but not in controls. Conclusions cfDNA offers promise as a non-invasive liquid-biopsy to evaluate liver-specific cell-death in patients with cholestatic liver diseases.
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Affiliation(s)
- Sohan Punia
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Brian D Juran
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Ahmad H Ali
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Erik M Schlicht
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Raymond M Moore
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, 55905, USA
| | - Zhifu Sun
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, 55905, USA
| | - Konstantinos N Lazaridis
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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25
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Hitomi Y, Aiba Y, Kawai Y, Kojima K, Ueno K, Nishida N, Kawashima M, Gervais O, Khor SS, Nagasaki M, Tokunaga K, Nakamura M, Tsuiji M. rs1944919 on chromosome 11q23.1 and its effector genes COLCA1/COLCA2 confer susceptibility to primary biliary cholangitis. Sci Rep 2021; 11:4557. [PMID: 33633225 PMCID: PMC7907150 DOI: 10.1038/s41598-021-84042-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 02/11/2021] [Indexed: 01/12/2023] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic, progressive cholestatic liver disease in which intrahepatic bile ducts are destroyed by an autoimmune reaction. Our previous genome-wide association study (GWAS) identified chromosome 11q23.1 as a susceptibility gene locus for PBC in the Japanese population. Here, high-density association mapping based on single nucleotide polymorphism (SNP) imputation and in silico/in vitro functional analyses identified rs1944919 as the primary functional variant. Expression-quantitative trait loci analyses showed that the PBC susceptibility allele of rs1944919 was significantly associated with increased COLCA1/COLCA2 expression levels. Additionally, the effects of rs1944919 on COLCA1/COLCA2 expression levels were confirmed using genotype knock-in versions of cell lines constructed using the CRISPR/Cas9 system and differed between rs1944919-G/G clones and -T/T clones. To our knowledge, this is the first study to demonstrate the contribution of COLCA1/COLCA2 to PBC susceptibility.
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Affiliation(s)
- Yuki Hitomi
- Department of Microbiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
| | - Yoshihiro Aiba
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan
| | - Yosuke Kawai
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
| | - Kaname Kojima
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Kazuko Ueno
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
| | - Nao Nishida
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan.,The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | | | - Olivier Gervais
- Human Biosciences Unit for the Top Global Course Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan
| | - Seik-Soon Khor
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
| | - Masao Nagasaki
- Human Biosciences Unit for the Top Global Course Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan
| | - Katsushi Tokunaga
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
| | - Minoru Nakamura
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan.,Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan.,Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Makoto Tsuiji
- Department of Microbiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
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26
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Abstract
Primary biliary cholangitis (PBC) causes chronic and persistent cholestasis in the liver, eventually resulting in cirrhosis and hepatic failure without appropriate treatment. PBC mainly develops in middle-aged women, but it is also common in young women and men. PBC is considered a model of autoimmune disease because of the presence of disease-specific autoantibodies, that is, antimitochondrial antibodies (AMAs), intense infiltration of mononuclear cells into the bile ducts, and a high prevalence of autoimmune diseases such as comorbidities. Histologically, PBC is characterized by degeneration and necrosis of intrahepatic biliary epithelial cells surrounded by a dense infiltration of mononuclear cells, coined as chronic non-suppurative destructive cholangitis, which leads to destructive changes and the disappearance of small- or medium-sized bile ducts. Since 1990, early diagnosis with the detection of AMAs and introduction of ursodeoxycholic acid as first-line treatment has greatly altered the clinical course of PBC, and liver transplantation-free survival of patients with PBC is now comparable to that of the general population.
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Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
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27
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Lleo A, Ma X, Gershwin ME, Invernizzi P. Letter to the Editor: Might Denosumab Fit in Primary Biliary Cholangitis Treatment? Hepatology 2020; 72:359-360. [PMID: 31863485 DOI: 10.1002/hep.31085] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Affiliation(s)
- Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Clinical and Research Center, IRCCS, Rozzano, Italy
| | - Xiong Ma
- Shanghai Institute of Digestive Disease, Renji Hospital, Jiao Tong University School of Medicine, Shanghai, China
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
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28
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Joshita S, Yamashita Y, Sugiura A, Uehara T, Usami Y, Yamazaki T, Fujimori N, Matsumoto A, Tanaka E, Umemura T. Clinical utility of FibroScan as a non-invasive diagnostic test for primary biliary cholangitis. J Gastroenterol Hepatol 2020; 35:1208-1214. [PMID: 31724755 DOI: 10.1111/jgh.14929] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 10/26/2019] [Accepted: 11/09/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM Primary biliary cholangitis (PBC) is a chronic, slowly progressive, autoimmune liver disease. Some PBC patients display disease progression regardless of medical treatment. Therefore, it is important to accurately diagnose the clinical stage of PBC. This study investigated clinical merits of vibration-controlled transient elastography using FibroScan for assessing disease stage in PBC. METHODS A total of 74 treatment-naïve PBC patients (84% female, median age: 64 years), 69 of whom having undergone histological assessment and five clinically diagnosed as at the cirrhosis stage, were enrolled for clinical comparisons of liver stiffness measurement (LSM) with other established indices. RESULTS The number of patients with Nakanuma stages 1, 2, 3, and 4 was 18, 33, 17, and 6, respectively. The median LSM values for Nakanuma stages 1, 2, 3, and 4 were 5.05, 5.90, 8.90, and 23.70 kPa, respectively, and correlated significantly with disease progression based on Nakanuma's classification (r = 0.501, P < 0.001). LSM was also significantly related to other non-invasive serological markers (Mac-2 binding protein glycosylation isomer: r = 0.606, FIB-4 index: r = 0.493, and aspartate aminotransferase-to-platelet ratio index: r = 0.577; all P < 0.001). The areas under the receiver operating characteristic curve for diagnosing Nakanuma stage ≥ 2, stage ≥ 3, and stage 4 were 0.744, 0.763, and 0.907, respectively. A combination of LSM ≥ 7.0 kPa and Mac-2 binding protein glycosylation isomer ≥ 1.00 cut-off index could predict late-stage PBC (i.e. moderate to advanced disease progression) with a sensitivity of 0.58, specificity of 0.82, and accuracy of 0.74. CONCLUSIONS Liver stiffness measurement using FibroScan provided simple, accurate, and non-invasive assessment of disease stage in PBC patients.
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Affiliation(s)
- Satoru Joshita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yuki Yamashita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Ayumi Sugiura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takeshi Uehara
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan
| | - Yoko Usami
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan
| | - Tomoo Yamazaki
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Naoyuki Fujimori
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Akihiro Matsumoto
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Eiji Tanaka
- Department for the Promotion of Regional Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takeji Umemura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan.,Department of Life Innovation, Institute for Biomedical Sciences, Shinshu University, Matsumoto, Japan
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29
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Olivier JF, Fodil N, Al Habyan S, Gopal A, Artusa P, Mandl JN, McCaffrey L, Gros P. CCDC88B is required for mobility and inflammatory functions of dendritic cells. J Leukoc Biol 2020; 108:1787-1802. [PMID: 32480428 DOI: 10.1002/jlb.3a0420-386r] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 04/13/2020] [Accepted: 05/08/2020] [Indexed: 12/17/2022] Open
Abstract
The Coiled Coil Domain Containing Protein 88B (CCDC88B) gene is associated with susceptibility to several inflammatory diseases in humans and its inactivation in mice protects against acute neuroinflammation and models of intestinal colitis. We report that mice lacking functional CCDC88B (Ccdc88bMut ) are defective in several dendritic cells (DCs)-dependent inflammatory and immune reactions in vivo. In these mice, an inflammatory stimulus (LPS) fails to induce the recruitment of DCs into the draining lymph nodes (LNs). In addition, OVA-pulsed Ccdc88bMut DCs injected in the footpad do not induce recruitment and activation of antigen-specific CD4+ and CD8+ T cells in their draining LN. Experiments in vitro indicate that this defect is independent of the ability of mutant DCs to capture and present peptide antigen to T cells. Rather, kinetic analyses in vivo of wild-type and Ccdc88bMut DCs indicate a reduced migration capacity in the absence of the CCDC88B protein expression. Moreover, using time-lapse light microscopy imaging, we show that Ccdc88bMut DCs have an intrinsic motility defect. Furthermore, in vivo studies reveal that these reduced migratory properties lead to dampened contact hypersensitivity reactions in Ccdc88b mutant mice. These findings establish a critical role of CCDC88B in regulating movement and migration of DCs. Thus, regulatory variants impacting Ccdc88b expression in myeloid cells may cause variable degrees of DC-dependent inflammatory response in situ, providing a rationale for the genetic association of CCDC88B with several inflammatory and autoimmune diseases in humans.
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Affiliation(s)
- Jean-Frederic Olivier
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada.,McGill Research Center for Complex Traits, McGill University, Montreal, Quebec, Canada
| | - Nassima Fodil
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada.,McGill Research Center for Complex Traits, McGill University, Montreal, Quebec, Canada
| | - Sara Al Habyan
- Department of Oncology, McGill University, Montreal, Quebec, Canada.,Goodman Cancer Research Center, McGill University, Montreal, Quebec, Canada
| | - Angelica Gopal
- McGill Research Center for Complex Traits, McGill University, Montreal, Quebec, Canada.,Department of Chemistry, McGill University, Montreal, Quebec, Canada.,Department of Physiology, McGill University, Montreal, Quebec, Canada
| | - Patricio Artusa
- McGill Research Center for Complex Traits, McGill University, Montreal, Quebec, Canada.,Department of Physiology, McGill University, Montreal, Quebec, Canada
| | - Judith N Mandl
- McGill Research Center for Complex Traits, McGill University, Montreal, Quebec, Canada.,Department of Physiology, McGill University, Montreal, Quebec, Canada
| | - Luke McCaffrey
- Department of Oncology, McGill University, Montreal, Quebec, Canada.,Goodman Cancer Research Center, McGill University, Montreal, Quebec, Canada
| | - Philippe Gros
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada.,McGill Research Center for Complex Traits, McGill University, Montreal, Quebec, Canada
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30
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Abstract
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with non-suppurative destruction of the intrahepatic bile ducts. The interplay of genetics and environmental triggers contributes to the onset of the disease and subsequently results in cholestasis and progressive fibrosis. Recently, genome-wide association studies (GWAS) have identified multiple genes influencing the susceptibility to PBC in HLA and non-HLA loci. However, it is estimated that the known risk variants merely account for no more than 20% of the heritability of PBC and causes of the remaining heritability remain uncertain. Increasing evidence suggests that the presence of epigenetic abnormalities may explain the "missing heritability" that cannot be captured by GWAS. Among these epigenetic mechanisms, DNA methylation, histone modification, and noncoding RNAs (i.e. miRNA and lncRNA) are involved in the pathogenesis of PBC. Additionally, telomere dysregulation in biliary epithelial cells (BECs) may play a role in disease onset, whereas a deficiency in sex chromosome and skewed gene expression in the X chromosome may to some extent explain the female dominance in PBC.
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31
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Li Y, Xi Y, Tao G, Xu G, Yang Z, Fu X, Liang Y, Qian J, Cui Y, Jiang T. Sirtuin 1 activation alleviates primary biliary cholangitis via the blocking of the NF-κB signaling pathway. Int Immunopharmacol 2020; 83:106386. [PMID: 32193100 DOI: 10.1016/j.intimp.2020.106386] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 03/05/2020] [Accepted: 03/05/2020] [Indexed: 12/12/2022]
Abstract
This report sought to establish the mechanistic role of sirtuin-1 (Sirt1), a NAD+-dependent deacetylase in the modulation of primary biliary cholangitis (PBC) pathogenesis. 64 PBC patients (diagnosed based on practice guidelines for American Association for the Study of Liver Diseases) and 60 healthy controls were included in this study. Clinically, the mRNA expression level of Sirt1 in macrophages differentiated from peripheral blood mononuclear cells (PBMCs) of PBC subjects substantially decreased when compared with the healthy controls but not in other Sirt family genes (Sirt2-7). Consistent with clinical results, a PBC murine model showed that levels of Sirt1 significantly decreased in the liver and Kupffer cells of mice treated with polyinosinic/polycytidylic acid (poly I:C) for 16 weeks. A TAK1 inhibitor (NG25) prevented the poly I:C-induced Sirt1 protein level decreasing in Kupffer cells but not MAPK inhibitor. Sirt1 activators resveratrol (RSV) and SRT1720 (SRT) ameliorated poly I:C-induced hepatic injury observed via histopathologic analysis and decreased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the PBC murine model. Furthermore, Sirt1 activators significantly reduced pro-inflammatory cytokines levels such as interleukin-1 beta (IL-1β), IL-6, interferon-gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) in serum in poly I:C-induced mice. In addition, Sirt1 activators significantly inhibited the phosphorylated and acetylated levels of the RelA/p65 subunit of the nuclear transcription factor (NF-κB) but not the interferon regulatory factor (IRF) 3 in poly I:C-injured mice livers. Significantly, RSV improved the interaction between Sirt1 and p65, which may contribute to the decreased activity of NF-κB. In summary, the Sirt1 signaling pathway plays an essential role in the development of PBC and this may represent a novel approach and target for the treatment of PBC.
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Affiliation(s)
- Yong Li
- Department of Laboratory Medicine, First People's Hospital of Taicang, Taicang Hospital Affiliated to Suzhou University, Taicang 215400, Jiangsu, China
| | - Yanhai Xi
- Department of Spine Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Guohua Tao
- Department of Laboratory Medicine, First People's Hospital of Nantong, 226001 Jiangsu, China
| | - Guohua Xu
- Department of Immunology and Microbiology, Institution of Laboratory Medicine of Changshu, Changshu 215500, Jiangsu, China
| | - Zaixing Yang
- Department of Laboratory Medicine, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Zhejiang, China
| | - Xingli Fu
- Jiangsu University Health Science Center, Zhenjiang, Jiangsu, China
| | - Yan Liang
- Department of Laboratory Diagnostics, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Jianping Qian
- Department of Immunology and Microbiology, Institution of Laboratory Medicine of Changshu, Changshu 215500, Jiangsu, China
| | - Yanhong Cui
- Department of Immunology and Microbiology, Institution of Laboratory Medicine of Changshu, Changshu 215500, Jiangsu, China
| | - Tingwang Jiang
- Department of Immunology and Microbiology, Institution of Laboratory Medicine of Changshu, Changshu 215500, Jiangsu, China.
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32
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Ueno K, Aiba Y, Hitomi Y, Shimoda S, Nakamura H, Gervais O, Kawai Y, Kawashima M, Nishida N, Kohn SS, Kojima K, Katsushima S, Naganuma A, Sugi K, Komatsu T, Mannami T, Matsushita K, Yoshizawa K, Makita F, Nikami T, Nishimura H, Kouno H, Kouno H, Ohta H, Komura T, Tsuruta S, Yamauchi K, Kobata T, Kitasato A, Kuroki T, Abiru S, Nagaoka S, Komori A, Yatsuhashi H, Migita K, Ohira H, Tanaka A, Takikawa H, Nagasaki M, Tokunaga K, Nakamura M. Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis. Hepatol Commun 2020; 4:724-738. [PMID: 32363322 PMCID: PMC7193132 DOI: 10.1002/hep4.1497] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 12/16/2019] [Accepted: 12/21/2019] [Indexed: 12/18/2022] Open
Abstract
Genome‐wide association studies (GWASs) in European and East Asian populations have identified more than 40 disease‐susceptibility genes in primary biliary cholangitis (PBC). The aim of this study is to computationally identify disease pathways, upstream regulators, and therapeutic targets in PBC through integrated GWAS and messenger RNA (mRNA) microarray analysis. Disease pathways and upstream regulators were analyzed with ingenuity pathway analysis in data set 1 for GWASs (1,920 patients with PBC and 1,770 controls), which included 261 annotated genes derived from 6,760 single‐nucleotide polymorphisms (P < 0.00001), and data set 2 for mRNA microarray analysis of liver biopsy specimens (36 patients with PBC and 5 normal controls), which included 1,574 genes with fold change >2 versus controls (P < 0.05). Hierarchical cluster analysis and categorization of cell type–specific genes were performed for data set 2. There were 27 genes, 10 pathways, and 149 upstream regulators that overlapped between data sets 1 and 2. All 10 pathways were immune‐related. The most significant common upstream regulators associated with PBC disease susceptibility identified were interferon‐gamma (IFNG) and CD40 ligand (CD40L). Hierarchical cluster analysis of data set 2 revealed two distinct groups of patients with PBC by disease activity. The most significant upstream regulators associated with disease activity were IFNG and CD40L. Several molecules expressed in B cells, T cells, Kupffer cells, and natural killer–like cells were identified as potential therapeutic targets in PBC with reference to a recently reported list of cell type–specific gene expression in the liver. Conclusion: Our integrated analysis using GWAS and mRNA microarray data sets predicted that IFNG and CD40L are the central upstream regulators in both disease susceptibility and activity of PBC and identified potential downstream therapeutic targets.
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Affiliation(s)
- Kazuko Ueno
- Genome Medical Science Project National Center for Global Health and Medicine Tokyo Japan.,Department of Human Genetics Graduate School of Medicine University of Tokyo Tokyo Japan
| | - Yoshihiro Aiba
- Clinical Research Center National Hospital Organization of Nagasaki Medical Center Omura Japan
| | - Yuki Hitomi
- Department of Human Genetics Graduate School of Medicine University of Tokyo Tokyo Japan.,Department of Microbiology Hoshi University School of Pharmacy and Pharmaceutical Sciences Tokyo Japan
| | - Shinji Shimoda
- Department of Medicine and Biosystemic Science Kyushu University Graduate School of Medical Sciences Fukuoka Japan
| | - Hitomi Nakamura
- Clinical Research Center National Hospital Organization of Nagasaki Medical Center Omura Japan
| | - Olivier Gervais
- Human Biosciences Unit for the Top Global Course Center for the Promotion of Interdisciplinary Education and Research Kyoto University Kyoto Japan
| | - Yosuke Kawai
- Genome Medical Science Project National Center for Global Health and Medicine Tokyo Japan.,Department of Human Genetics Graduate School of Medicine University of Tokyo Tokyo Japan
| | | | - Nao Nishida
- Genome Medical Science Project National Center for Global Health and Medicine Tokyo Japan.,Department of Human Genetics Graduate School of Medicine University of Tokyo Tokyo Japan
| | - Seik-Soon Kohn
- Genome Medical Science Project National Center for Global Health and Medicine Tokyo Japan.,Department of Human Genetics Graduate School of Medicine University of Tokyo Tokyo Japan
| | - Kaname Kojima
- Tohoku Medical Megabank Organization Tohoku University Sendai Japan
| | - Shinji Katsushima
- Headquarters of PBC Research National Hospital Organization Study Group for Liver Disease in Japan Omura Japan
| | - Atsushi Naganuma
- Headquarters of PBC Research National Hospital Organization Study Group for Liver Disease in Japan Omura Japan
| | - Kazuhiro Sugi
- Headquarters of PBC Research National Hospital Organization Study Group for Liver Disease in Japan Omura Japan
| | - Tatsuji Komatsu
- Headquarters of PBC Research National Hospital Organization Study Group for Liver Disease in Japan Omura Japan
| | - Tomohiko Mannami
- Headquarters of PBC Research National Hospital Organization Study Group for Liver Disease in Japan Omura Japan
| | - Kouki Matsushita
- Headquarters of PBC Research National Hospital Organization Study Group for Liver Disease in Japan Omura Japan
| | - Kaname Yoshizawa
- Headquarters of PBC Research National Hospital Organization Study Group for Liver Disease in Japan Omura Japan
| | - Fujio Makita
- Headquarters of PBC Research National Hospital Organization Study Group for Liver Disease in Japan Omura Japan
| | - Toshiki Nikami
- Headquarters of PBC Research National Hospital Organization Study Group for Liver Disease in Japan Omura Japan
| | - Hideo Nishimura
- Headquarters of PBC Research National Hospital Organization Study Group for Liver Disease in Japan Omura Japan
| | - Hiroshi Kouno
- Headquarters of PBC Research National Hospital Organization Study Group for Liver Disease in Japan Omura Japan
| | - Hirotaka Kouno
- Headquarters of PBC Research National Hospital Organization Study Group for Liver Disease in Japan Omura Japan
| | - Hajime Ohta
- Headquarters of PBC Research National Hospital Organization Study Group for Liver Disease in Japan Omura Japan
| | - Takuya Komura
- Headquarters of PBC Research National Hospital Organization Study Group for Liver Disease in Japan Omura Japan
| | - Satoru Tsuruta
- Headquarters of PBC Research National Hospital Organization Study Group for Liver Disease in Japan Omura Japan
| | - Kazuhiko Yamauchi
- Headquarters of PBC Research National Hospital Organization Study Group for Liver Disease in Japan Omura Japan
| | - Tatsuro Kobata
- Headquarters of PBC Research National Hospital Organization Study Group for Liver Disease in Japan Omura Japan
| | - Amane Kitasato
- Department of Surgery National Hospital Organization of Nagasaki Medical Center Omura Japan
| | - Tamotsu Kuroki
- Clinical Research Center National Hospital Organization of Nagasaki Medical Center Omura Japan.,Department of Surgery National Hospital Organization of Nagasaki Medical Center Omura Japan.,Department of Hepatology Graduate School of Biomedical Sciences Nagasaki University Omura Japan
| | - Seigo Abiru
- Clinical Research Center National Hospital Organization of Nagasaki Medical Center Omura Japan
| | - Shinya Nagaoka
- Clinical Research Center National Hospital Organization of Nagasaki Medical Center Omura Japan
| | - Atsumasa Komori
- Clinical Research Center National Hospital Organization of Nagasaki Medical Center Omura Japan.,Department of Hepatology Graduate School of Biomedical Sciences Nagasaki University Omura Japan
| | - Hiroshi Yatsuhashi
- Clinical Research Center National Hospital Organization of Nagasaki Medical Center Omura Japan.,Department of Hepatology Graduate School of Biomedical Sciences Nagasaki University Omura Japan
| | - Kiyoshi Migita
- Clinical Research Center National Hospital Organization of Nagasaki Medical Center Omura Japan.,Department of Gastroenterology and Rheumatic Diseases Fukushima Medical University of Medicine Fukushima Japan
| | - Hiromasa Ohira
- Department of Gastroenterology and Rheumatic Diseases Fukushima Medical University of Medicine Fukushima Japan
| | - Atsushi Tanaka
- Department of Medicine Teikyo University School of Medicine Tokyo Japan
| | - Hajime Takikawa
- Department of Medicine Teikyo University School of Medicine Tokyo Japan
| | - Masao Nagasaki
- Human Biosciences Unit for the Top Global Course Center for the Promotion of Interdisciplinary Education and Research Kyoto University Kyoto Japan
| | - Katsushi Tokunaga
- Genome Medical Science Project National Center for Global Health and Medicine Tokyo Japan.,Department of Human Genetics Graduate School of Medicine University of Tokyo Tokyo Japan
| | - Minoru Nakamura
- Clinical Research Center National Hospital Organization of Nagasaki Medical Center Omura Japan.,Headquarters of PBC Research National Hospital Organization Study Group for Liver Disease in Japan Omura Japan.,Department of Hepatology Graduate School of Biomedical Sciences Nagasaki University Omura Japan.,Headquarters of PBC-GWAS Consortium in Japan National Hospital Organization of Nagasaki Medical Center Graduate School of Biomedical Sciences Nagasaki University Omura Japan
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33
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Wang C, Zheng X, Tang R, Han C, Jiang Y, Wu J, Shao Y, Gao Y, Yu J, Hu Z, Zang Z, Zhao Y, Dai N, Liu L, Wu X, Nie J, Jiang B, Lin M, Li L, Wei Y, Li Y, Gong Y, Dai Y, Wang L, Ding N, Xu P, Chen S, Jiang P, Wang L, Qiu F, Wu Q, Zhang M, Jawed R, Chen R, Zhang Y, Shi X, Zhu Z, Pei H, Huang L, Tian Y, Zhang K, Qiu H, Zhao W, Gershwin ME, Chen W, Seldin MF, Liu X, Ma X, Sun L. Fine mapping of the MHC region identifies major independent variants associated with Han Chinese primary biliary cholangitis. J Autoimmun 2020; 107:102372. [PMID: 31810856 DOI: 10.1016/j.jaut.2019.102372] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 11/03/2019] [Accepted: 11/14/2019] [Indexed: 02/08/2023]
Abstract
The genetic association of primary biliary cholangitis with major histocompatibility complex (MHC) has been widely confirmed among different ethnicities. To map specific MHC region variants associated with PBC in a Han Chinese cohort, we imputed HLA antigens and amino acids (AA) in 1126 PBC cases and 1770 healthy control subjects using a Han-MHC reference database. We demonstrate that HLA-DRB1 and/or HLA-DQB1 contributed the strongest signals, and that HLA-DPB1 was a separate independent locus. Regression analyses with classical HLA alleles indicate that HLA-DQB1*03:01 or HLA-DQβ1-Pro55, HLA-DPB1*17:01 or HLA-DPβ1-Asp84 and HLA-DRB1*08:03 could largely explain MHC association with PBC. Forward stepwise regression analyses with HLA amino acid variants localize the major signals to HLA-DRβ1-Ala74, HLA-DQβ1-Pro55 and HLA-DPβ1-Asp84. Electrostatic potential calculations implicated AA variations at HLA-DQβ1 position 55 and HLA-DPβ1 position 84 as critical to peptide binding properties. Furthermore, although several critical Han Chinese AA variants differed from those shown in European populations, the predicted effects on antigen binding are likely to be very similar or identical and underlie the major component of MHC association with PBC.
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Affiliation(s)
- Chan Wang
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Xiaodong Zheng
- Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China, Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China, Key Laboratory of Major Autoimmune Diseases, Anhui Province, Hefei, China, 218 Jixi Road, Hefei, Anhui, 230022, China
| | - Ruqi Tang
- Department of Gastroenterology and Hepatology, Shanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, 145 Shandong Middle Road, Shanghai, 200001, China
| | - Chongxu Han
- Department of Laboratory Medicine, Subei People's Hospital, Clinical Medical College, Yangzhou University, 98 Nantong West Road, Yangzhou, Jiangsu, 225001, China
| | - Yuzhang Jiang
- Department of Laboratory Medicine, Huai'an First People's Hospital, Nanjing Medical University, 1 Huanghe West Road, Huai'an, Jiangsu, 223300, China
| | - Jian Wu
- Department of Rheumatology, First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, Jiangsu, 215006, China
| | - Youlin Shao
- Department of Hepatology, The Third People's Hospital of Changzhou, 300 Lanling North Road, Changzhou, Jiangsu, 213001, China
| | - Yueqiu Gao
- Department of Liver Disease, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Jianjiang Yu
- Department of Laboratory Medicine, Jiangyin People's Hospital, Southeast University, 163 Shoushan Road, Jiangyin, Jiangsu, 214400, China
| | - Zhigang Hu
- Department of Laboratory Medicine, Affiliated Wuxi People's Hospital of Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu, 214023, China
| | - Zhidong Zang
- Department of Hepatology, The Second Hospital of Nanjing, Southeast University, 1 Zhongfu Road, Nanjing, jiangsu, 210003, China
| | - Yi Zhao
- Department of Gastrointestinal Endoscopy, Eastern Hepatobiliary Surgery Hospital, 700 Moyu North Road, Shanghai, 201800, China
| | - Na Dai
- Department of Gastroenterology, Jiangsu University Affiliated Kunshan Hospital, 91 Qianjin West Road, Kunshan, Jiangsu, 215300, China
| | - Lei Liu
- Department of Gastroenterology, Yixing People's Hospital, 75 Tongzhenguan Road, Yixing, Jiangsu, 214200, China
| | - Xudong Wu
- Department of Gastroenterology, Yancheng First People's Hospital, 66 Renmin South Road, Yancheng, Jiangsu, 224005, China
| | - Jinshan Nie
- Department of Gastroenterology, Taicang First People's Hospital, Soochow University, 58 Changsheng South Road, Taicang, Jiangsu, 215400, China
| | - Bo Jiang
- Department of Hepatology, Jingjiang Second People's Hospital, 1 Chengxiqiao Jiangping Road, Jingjiang, Jiangsu, 214500, China
| | - Maosong Lin
- Department of Gastroenterology, Taizhou People's Hospital, 210 Yingchun Road, Taizhou, Jiangsu, 225300, China
| | - Li Li
- Department of Laboratory Medicine, Zhongda Hospital, Southeast University, 87 Dingjiaqiao Road, Nanjing, Jiangsu, 210009, China
| | - Yiran Wei
- Department of Gastroenterology and Hepatology, Shanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, 145 Shandong Middle Road, Shanghai, 200001, China
| | - You Li
- Department of Gastroenterology and Hepatology, Shanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, 145 Shandong Middle Road, Shanghai, 200001, China
| | - Yuhua Gong
- Department of Laboratory Medicine, The Third People's Hospital of Zhenjiang, 300 Daijiamen, Zhenjiang, Jiangsu, 212021, China
| | - Yaping Dai
- Department of Laboratory Medicine, The Fifth People's Hospital of Wuxi, 1215 Guangrui Road, Wuxi, Jiangsu, 214000, China
| | - Lan Wang
- Department of Laboratory Medicine, The 81st Hospital of PLA, 34 Yanggongjing Nanjing, Jiangsu, 210002, China
| | - Ningling Ding
- Department of Hepatology, Department of Laboratory Medicine, The Fifth People's Hospital of Suzhou, Soochow University, 10 Guangqian Road, Suzhou, Jiangsu, 215131, China
| | - Ping Xu
- Department of Radiology, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu, 215004, China
| | - Sufang Chen
- Department of Hepatology, Department of Laboratory Medicine, The Fifth People's Hospital of Suzhou, Soochow University, 10 Guangqian Road, Suzhou, Jiangsu, 215131, China
| | - Peng Jiang
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Lu Wang
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Fang Qiu
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Qiuyuan Wu
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Mingming Zhang
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Rohil Jawed
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Ru Chen
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Yu Zhang
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Xingjuan Shi
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China
| | - Zhen Zhu
- Department of Hepatology, The Third People's Hospital of Changzhou, 300 Lanling North Road, Changzhou, Jiangsu, 213001, China
| | - Hao Pei
- Department of Laboratory Medicine, The Fifth People's Hospital of Wuxi, 1215 Guangrui Road, Wuxi, Jiangsu, 214000, China
| | - Lihua Huang
- Department of Laboratory Medicine, The Fifth People's Hospital of Wuxi, 1215 Guangrui Road, Wuxi, Jiangsu, 214000, China
| | - Ye Tian
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, Jiangsu, 210008, China
| | - Kui Zhang
- Department of Hepatology, First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, Jiangsu, 215006, China
| | - Hong Qiu
- Department of Laboratory Medicine, The 81st Hospital of PLA, 34 Yanggongjing Nanjing, Jiangsu, 210002, China
| | - Weifeng Zhao
- Department of Hepatology, First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, Jiangsu, 215006, China
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Genome and Biomedical Sciences Facility Building, 451 Health Sciences Drive, Suite 6510, Davis, CA, 95616, USA
| | - Weichang Chen
- Department of Gastroenterology, First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, Jiangsu, 215006, China
| | - Michael F Seldin
- Department of Biochemistry and Molecular Medicine, University of California at Davis School of Medicine, 4327 Tupper Hall, Davis, CA, 95616, USA
| | - Xiangdong Liu
- Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu, 210096, China.
| | - Xiong Ma
- Department of Gastroenterology and Hepatology, Shanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, 145 Shandong Middle Road, Shanghai, 200001, China.
| | - Liangdan Sun
- Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China, Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China, Key Laboratory of Major Autoimmune Diseases, Anhui Province, Hefei, China, 218 Jixi Road, Hefei, Anhui, 230022, China.
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34
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Dong X, Yu X, Li H, Kang H. Identification of Marker Genes and Pathways in Patients with Primary Biliary Cholangitis. J Comput Biol 2019; 27:923-933. [PMID: 31638426 DOI: 10.1089/cmb.2019.0230] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by cholestasis and cirrhosis, and in which hepatic failure may occur. This study explores the changes in the gene expression profiles of liver tissues during the pathogenesis of PBC. Array dataset GSE79850 was downloaded from the Gene Expression Omnibus database. GeneSpring software was used to analyze differentially expressed genes (DEGs) in liver tissues from PBC patients compared with those from controls. Gene ontology (GO) annotation, the Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway enrichment analyses were performed by using Database for Annotation, Visualization and Integrated Discovery (DAVID) software. Cytoscape software was used to construct a protein-protein interaction (PPI) network. Plug-ins Molecular Complex Detection and iRegulon were used for clustering analysis and transcription factors related to key genes with PBC. A total of 77 DEGs, including 47 up- and 30 downregulated genes, were identified. The PPI network was established with 74 nodes and 356 protein pairs. The C-C motif chemokine ligand 5 (CCL5), interleukin 7 receptor (IL7R), and TNF receptor superfamily member 1A (TNFRSF1A) were identified as hub genes in the PPI network and may, therefore, be marker genes for PBC. Further, the upregulated genes CCL5 and IL7R, and downregulated TNFRSF1A were included in immune system processes as a GO term in the category Biological Processes. In conclusion, CCL5, IL7R, TNFRSF1A, and the immune response pathway may have crucial roles in PBC. These genes and pathways may be potential targets for treating PBC.
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Affiliation(s)
- Xihua Dong
- Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xiaoou Yu
- Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Hua Li
- Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Hui Kang
- Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China
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35
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D, Vierling JM, Adams D, Alpini G, Banales JM, Beuers U, Björnsson E, Bowlus C, Carbone M, Chazouillères O, Dalekos G, De Gottardi A, Harada K, Hirschfield G, Invernizzi P, Jones D, Krawitt E, Lanzavecchia A, Lian ZX, Ma X, Manns M, Mavilio D, Quigley EM, Sallusto F, Shimoda S, Strazzabosco M, Swain M, Tanaka A, Trauner M, Tsuneyama K, Zigmond E, Gershwin ME. The challenges of primary biliary cholangitis: What is new and what needs to be done. J Autoimmun 2019; 105:102328. [PMID: 31548157 DOI: 10.1016/j.jaut.2019.102328] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 08/18/2019] [Accepted: 08/20/2019] [Indexed: 02/06/2023]
Abstract
Primary Biliary Cholangitis (PBC) is an uncommon, chronic, cholangiopathy of autoimmune origin and unknown etiology characterized by positive anti-mitochondrial autoantibodies (AMA), female preponderance and progression to cirrhosis if left untreated. The diagnosis is based on AMA- or PBC-specific anti-nuclear antibody (ANA)-positivity in the presence of a cholestatic biochemical profile, histologic confirmation being mandatory only in seronegative cases. First-line treatment is ursodeoxycholic acid (UDCA), which is effective in preventing disease progression in about two thirds of the patients. The only approved second-line treatment is obeticholic acid. This article summarizes the most relevant conclusions of a meeting held in Lugano, Switzerland, from September 23rd-25th 2018, gathering basic and clinical scientists with various background from around the world to discuss the latest advances in PBC research. The meeting was dedicated to Ian Mackay, pioneer in the field of autoimmune liver diseases. The role of liver histology needs to be reconsidered: liver pathology consistent with PBC in AMA-positive individuals without biochemical cholestasis is increasingly reported, raising the question as to whether biochemical cholestasis is a reliable disease marker for both clinical practice and trials. The urgent need for new biomarkers, including more accurate markers of cholestasis, was also widely discussed during the meeting. Moreover, new insights in interactions of bile acids with biliary epithelia in PBC provide solid evidence of a role for impaired epithelial protection against potentially toxic hydrophobic bile acids, raising the fundamental question as to whether this bile acid-induced epithelial damage is the cause or the consequence of the autoimmune attack to the biliary epithelium. Strategies are needed to identify difficult-to-treat patients at an early disease stage, when new therapeutic approaches targeting immunologic pathways, in addition to bile acid-based therapies, may be effective. In conclusion, using interdisciplinary approaches, groundbreaking advances can be expected before long in respect to our understanding of the etiopathogenesis of PBC, with the ultimate aim of improving its treatment.
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Affiliation(s)
- Benedetta Terziroli Beretta-Piccoli
- Epatocentro Ticino, Lugano, Switzerland; Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK; European Reference Network ERN RARE-LIVER.
| | - Giorgina Mieli-Vergani
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, London, UK
| | - Diego Vergani
- Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK
| | - John M Vierling
- Division of Abdominal Transplantation and Section of Gastroenterology and Hepatology, Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX, USA
| | - David Adams
- Birmingham NIHR Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental SciencesMedical School, University of Birmingham, Birmingham, UK
| | - Gianfranco Alpini
- Indiana Center for Liver Research, Richard L. Roudebush VA Medical Center and Indiana University, Indianapolis, IN, USA
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, Ikerbasque, San Sebastián, Spain
| | - Ulrich Beuers
- European Reference Network ERN RARE-LIVER; Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Einar Björnsson
- Division of Gastroenterology and Hepatology, Landspitali the National University Hospital of Iceland, Reykjavík, Iceland
| | - Christopher Bowlus
- Division of Gastroenterology and Hepatology, University of California at Davis School of Medicine, Davis, CA, USA
| | - Marco Carbone
- Division Gastroenterology and Center for Autoimmune Liver Diseases, University of Milan-Bicocca School of Medicine, Monza, Italy
| | - Olivier Chazouillères
- European Reference Network ERN RARE-LIVER; Service d'Hépatologie, Hôpital Saint-Antoine, Paris, France
| | - George Dalekos
- Institute of Internal Medicine and Hepatology, Department of Medicine and Research, Laboratory of Internal Medicine, School of Medicine, University of Thessaly, Larissa, Greece
| | - Andrea De Gottardi
- European Reference Network ERN RARE-LIVER; Epatocentro Ticino & Division of Gastroenterology and Hepatology Ente Ospedaliero Cantonale and Università della Svizzera Italiana, Lugano, Switzerland
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Gideon Hirschfield
- Toronto Centre for Liver Disease, University Health Network and University of Toronto, Toronto, Canada
| | - Pietro Invernizzi
- European Reference Network ERN RARE-LIVER; Division Gastroenterology and Center for Autoimmune Liver Diseases, University of Milan-Bicocca School of Medicine, Monza, Italy
| | - David Jones
- Institute of Cellular Medicine and NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, UK
| | - Edward Krawitt
- Department of Medicine, University of Vermont, Burlington, VT, USA
| | | | - Zhe-Xiong Lian
- Institutes for Life Sciences, South China University of Technology, Higher Education Mega Center, Guangzhou, China
| | - Xiong Ma
- Shanghai Institute of Digestive Disease, Renji Hospital, Jiao Tong University School of Medicine, Shanghai, China
| | - Michael Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
| | - Domenico Mavilio
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Italy
| | - Eamon Mm Quigley
- Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX, USA
| | - Federica Sallusto
- Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland
| | - Shinji Shimoda
- Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Mario Strazzabosco
- Liver Center, Department of Medicine, Yale University, New Haven, CT, USA
| | - Mark Swain
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Ehud Zigmond
- Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, California, USA.
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Das T, Bergen IM, Koudstaal T, van Hulst JA, van Loo G, Boonstra A, Vanwolleghem T, Leung PS, Gershwin ME, Hendriks RW, Kool M. DNGR1-mediated deletion of A20/Tnfaip3 in dendritic cells alters T and B-cell homeostasis and promotes autoimmune liver pathology. J Autoimmun 2019; 102:167-178. [DOI: 10.1016/j.jaut.2019.05.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 04/27/2019] [Accepted: 05/05/2019] [Indexed: 02/06/2023]
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Abstract
PURPOSE OF REVIEW Primary biliary cholangitis (PBC) is a female predominant chronic autoimmune disease of the intrahepatic bile ducts and with a long latent period. It is crucial to understand how genetics contribute to the disease. RECENT FINDINGS Geo-epidemiological studies in PBC have provided evidence of familial risk; case-control studies and genome wide association studies have identified various human leukocyte antigen (HLA) and non-HLA alleles that are associated with PBC. However, these alleles are non-PBC specific and most of the identified non-HLA loci were also found to be susceptible genes in other autoimmune diseases and different between study populations. SUMMARY Patients with PBC are often asymptomatic and often left undiagnosed. There are no known HLA and non-HLA alleles specific for PBC. Global effort and novel approaches such as epigenetics directed at identification of genetic risk factors will greatly facilitate accurate and timely diagnosis, which will improve prognosis and increase treatment options.
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38
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Epigenetics of autoimmune liver diseases: current progress and future directions. JOURNAL OF BIO-X RESEARCH 2019. [DOI: 10.1097/jbr.0000000000000030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Hitomi Y, Ueno K, Kawai Y, Nishida N, Kojima K, Kawashima M, Aiba Y, Nakamura H, Kouno H, Kouno H, Ohta H, Sugi K, Nikami T, Yamashita T, Katsushima S, Komeda T, Ario K, Naganuma A, Shimada M, Hirashima N, Yoshizawa K, Makita F, Furuta K, Kikuchi M, Naeshiro N, Takahashi H, Mano Y, Yamashita H, Matsushita K, Tsunematsu S, Yabuuchi I, Nishimura H, Shimada Y, Yamauchi K, Komatsu T, Sugimoto R, Sakai H, Mita E, Koda M, Nakamura Y, Kamitsukasa H, Sato T, Nakamuta M, Masaki N, Takikawa H, Tanaka A, Ohira H, Zeniya M, Abe M, Kaneko S, Honda M, Arai K, Arinaga-Hino T, Hashimoto E, Taniai M, Umemura T, Joshita S, Nakao K, Ichikawa T, Shibata H, Takaki A, Yamagiwa S, Seike M, Sakisaka S, Takeyama Y, Harada M, Senju M, Yokosuka O, Kanda T, Ueno Y, Ebinuma H, Himoto T, Murata K, Shimoda S, Nagaoka S, Abiru S, Komori A, Migita K, Ito M, Yatsuhashi H, Maehara Y, Uemoto S, Kokudo N, Nagasaki M, Tokunaga K, Nakamura M. POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33. Sci Rep 2019; 9:102. [PMID: 30643196 PMCID: PMC6331557 DOI: 10.1038/s41598-018-36490-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 11/13/2018] [Indexed: 12/28/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic and cholestatic autoimmune liver disease caused by the destruction of intrahepatic small bile ducts. Our previous genome-wide association study (GWAS) identified six susceptibility loci for PBC. Here, in order to further elucidate the genetic architecture of PBC, a GWAS was performed on an additional independent sample set, then a genome-wide meta-analysis with our previous GWAS was performed based on a whole-genome single nucleotide polymorphism (SNP) imputation analysis of a total of 4,045 Japanese individuals (2,060 cases and 1,985 healthy controls). A susceptibility locus on chromosome 3q13.33 (including ARHGAP31, TMEM39A, POGLUT1, TIMMDC1, and CD80) was previously identified both in the European and Chinese populations and was replicated in the Japanese population (OR = 0.7241, P = 3.5 × 10-9). Subsequent in silico and in vitro functional analyses identified rs2293370, previously reported as the top-hit SNP in this locus in the European population, as the primary functional SNP. Moreover, e-QTL analysis indicated that the effector gene of rs2293370 was Protein O-Glucosyltransferase 1 (POGLUT1) (P = 3.4 × 10-8). This is the first study to demonstrate that POGLUT1 and not CD80 is the effector gene regulated by the primary functional SNP rs2293370, and that increased expression of POGLUT1 might be involved in the pathogenesis of PBC.
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Affiliation(s)
- Yuki Hitomi
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Kazuko Ueno
- Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Yosuke Kawai
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Nao Nishida
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Kaname Kojima
- Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Graduate School of Medicine, Tohoku University, Sendai, Japan
| | | | - Yoshihiro Aiba
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan
| | - Hitomi Nakamura
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan
| | - Hiroshi Kouno
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Hirotaka Kouno
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Hajime Ohta
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Kazuhiro Sugi
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Toshiki Nikami
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Tsutomu Yamashita
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Shinji Katsushima
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Toshiki Komeda
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Keisuke Ario
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Atsushi Naganuma
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Masaaki Shimada
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Noboru Hirashima
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Kaname Yoshizawa
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Fujio Makita
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Kiyoshi Furuta
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Masahiro Kikuchi
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Noriaki Naeshiro
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Hironao Takahashi
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Yutaka Mano
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Haruhiro Yamashita
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Kouki Matsushita
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Seiji Tsunematsu
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Iwao Yabuuchi
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Hideo Nishimura
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Yusuke Shimada
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Kazuhiko Yamauchi
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Tatsuji Komatsu
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Rie Sugimoto
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Hironori Sakai
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Eiji Mita
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Masaharu Koda
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Yoko Nakamura
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Hiroshi Kamitsukasa
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Takeaki Sato
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Makoto Nakamuta
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Naohiko Masaki
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Hajime Takikawa
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology and Rheumatic Diseases, Fukushima Medical University of Medicine, Fukushima, Japan
| | - Mikio Zeniya
- Department of Gastroenterology and Hepatology, Tokyo Jikei University School of Medicine, Tokyo, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Teruko Arinaga-Hino
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Etsuko Hashimoto
- Department of Medicine and Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Makiko Taniai
- Department of Medicine and Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Takeji Umemura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Satoru Joshita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tatsuki Ichikawa
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hidetaka Shibata
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Satoshi Yamagiwa
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | | | - Shotaro Sakisaka
- Department of Gastroenterology and Medicine, Fukuoka University School of Medicine, Fukuoka, Japan
| | - Yasuaki Takeyama
- Department of Gastroenterology and Medicine, Fukuoka University School of Medicine, Fukuoka, Japan
| | - Masaru Harada
- The Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Michio Senju
- The Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Osamu Yokosuka
- Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tatsuo Kanda
- Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Hirotoshi Ebinuma
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio Graduate School of Medicine, Tokyo, Japan
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Kagawa, Japan
| | - Kazumoto Murata
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Shinji Shimoda
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Shinya Nagaoka
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan
| | - Seigo Abiru
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan
| | - Atsumasa Komori
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan
| | - Kiyoshi Migita
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan
| | - Masahiro Ito
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan
| | - Hiroshi Yatsuhashi
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Shinji Uemoto
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Norihiro Kokudo
- National Center for Global Health and Medicine, Tokyo, Japan
| | - Masao Nagasaki
- Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Graduate School of Medicine, Tohoku University, Sendai, Japan
- Graduate School of Information Sciences, Tohoku University, Sendai, Japan
| | - Katsushi Tokunaga
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Minoru Nakamura
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan.
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan.
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan.
- Headquaters of PBC-GWAS study group in Japan, Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan.
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Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology 2019; 69:394-419. [PMID: 30070375 DOI: 10.1002/hep.30145] [Citation(s) in RCA: 400] [Impact Index Per Article: 66.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 05/30/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Keith D Lindor
- Arizona State University, Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ
| | | | | | | | - Marlyn Mayo
- University of Texas Southwestern Medical Center, Dallas, TX
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Hitomi Y, Nakatani K, Kojima K, Nishida N, Kawai Y, Kawashima M, Aiba Y, Nagasaki M, Nakamura M, Tokunaga K. NFKB1 and MANBA Confer Disease Susceptibility to Primary Biliary Cholangitis via Independent Putative Primary Functional Variants. Cell Mol Gastroenterol Hepatol 2018; 7:515-532. [PMID: 30528300 PMCID: PMC6396435 DOI: 10.1016/j.jcmgh.2018.11.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 11/18/2018] [Accepted: 11/19/2018] [Indexed: 01/03/2023]
Abstract
BACKGROUND & AIMS Primary biliary cholangitis (PBC) is a chronic and cholestatic liver disease that eventually leads to cirrhosis and hepatic failure. We recently identified several susceptibility genes included NFKB1 and MANBA for PBC in the Japanese population by genome-wide association study. However, the primary functional variants in the NFKB1/MANBA region and the molecular mechanism for conferring disease susceptibility to PBC have not yet been clarified. METHODS We performed high-density association mapping based on a single-nucleotide polymorphism (SNP) imputation analysis, using data from a whole-genome sequence reference panel of 1070 Japanese individuals and the previous genome-wide association study (1389 PBC patients, 1508 healthy controls). Among SNPs (P < 5.0 × 10-7) in the NFKB1/MANBA region, putative primary functional variants and the molecular mechanism for conferring disease susceptibility to PBC were identified by in silico/in vitro functional analysis. RESULTS Among the SNPs in the NFKB1/MANBA region, rs17032850 and rs227361, which changed the binding of transcription factors lymphoid enhancer-binding factor 1 (LEF-1) and retinoid X receptor α (RXRα), respectively, were identified as putative primary functional variants that regulate gene expression. In addition, expression-quantitative trait locus data and gene editing using a clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system supported the potential role of rs17032850 and rs227361 in regulating NFKB1 and MANBA expression, respectively. CONCLUSIONS We identified independent putative primary functional variants in NFKB1/MANBA and showed the distinct molecular mechanism by which each putative primary functional variant conferred susceptibility to PBC. Our approach was useful to dissect the pathogenesis not only of PBC, but also other digestive diseases in which NFKB1/MANBA has been reported as a susceptibility locus.
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Affiliation(s)
- Yuki Hitomi
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan,Correspondence Address correspondence to: Yuki Hitomi, PhD, Department of Human Genetics, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. fax: (81) 3-5802-8619.
| | - Ken Nakatani
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Kaname Kojima
- Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan,Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Nao Nishida
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan,The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Yosuke Kawai
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan,Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan,Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Minae Kawashima
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan,Japan Science and Technology Agency, Tokyo, Japan
| | - Yoshihiro Aiba
- Clinical Research Center, National Hospital Organization, Nagasaki Medical Center, Omura, Japan
| | - Masao Nagasaki
- Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan,Graduate School of Medicine, Tohoku University, Sendai, Japan,Graduate School of Information Sciences, Tohoku University, Sendai, Japan
| | - Minoru Nakamura
- Headquarters of Primary Biliary Cholangitis (PBC) Research in National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, National Hospital Organization, Nagasaki Medical Center, Omura, Japan,Clinical Research Center, National Hospital Organization, Nagasaki Medical Center, Omura, Japan,Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Katsushi Tokunaga
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
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Gerussi A, Cristoferi L, Carbone M, Asselta R, Invernizzi P. The immunobiology of female predominance in primary biliary cholangitis. J Autoimmun 2018; 95:124-132. [DOI: 10.1016/j.jaut.2018.10.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 10/17/2018] [Indexed: 12/21/2022]
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Rojas M, Restrepo-Jiménez P, Monsalve DM, Pacheco Y, Acosta-Ampudia Y, Ramírez-Santana C, Leung PS, Ansari AA, Gershwin ME, Anaya JM. Molecular mimicry and autoimmunity. J Autoimmun 2018; 95:100-123. [DOI: 10.1016/j.jaut.2018.10.012] [Citation(s) in RCA: 214] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 10/12/2018] [Accepted: 10/16/2018] [Indexed: 12/15/2022]
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Darlay R, Ayers KL, Mells GF, Hall LS, Liu JZ, Almarri MA, Alexander GJ, Jones DE, Sandford RN, Anderson CA, Cordell HJ. Amino acid residues in five separate HLA genes can explain most of the known associations between the MHC and primary biliary cholangitis. PLoS Genet 2018; 14:e1007833. [PMID: 30507971 PMCID: PMC6292650 DOI: 10.1371/journal.pgen.1007833] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 12/13/2018] [Accepted: 11/13/2018] [Indexed: 12/15/2022] Open
Abstract
Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterised by progressive destruction of intrahepatic bile ducts. The strongest genetic association is with HLA-DQA1*04:01, but at least three additional independent HLA haplotypes contribute to susceptibility. We used dense single nucleotide polymorphism (SNP) data in 2861 PBC cases and 8514 controls to impute classical HLA alleles and amino acid polymorphisms using state-of-the-art methodologies. We then demonstrated through stepwise regression that association in the HLA region can be largely explained by variation at five separate amino acid positions. Three-dimensional modelling of protein structures and calculation of electrostatic potentials for the implicated HLA alleles/amino acid substitutions demonstrated a correlation between the electrostatic potential of pocket P6 in HLA-DP molecules and the HLA-DPB1 alleles/amino acid substitutions conferring PBC susceptibility/protection, highlighting potential new avenues for future functional investigation.
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Affiliation(s)
- Rebecca Darlay
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Kristin L. Ayers
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - George F. Mells
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom
| | - Lynsey S. Hall
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
- Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Jimmy Z. Liu
- Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, United Kingdom
| | - Mohamed A. Almarri
- Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, United Kingdom
- Department of Forensic Science and Criminology, Dubai Police HQ, Dubai, United Arab Emirates
| | - Graeme J. Alexander
- Department of Hepatology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, United Kingdom
| | - David E. Jones
- Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Richard N. Sandford
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom
| | - Carl A. Anderson
- Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, United Kingdom
| | - Heather J. Cordell
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
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Mantaka A, Koulentaki M, Samonakis D, Sifaki-Pistolla D, Voumvouraki A, Tzardi M, Kouroumalis E. Association of smoking with liver fibrosis and mortality in primary biliary cholangitis. Eur J Gastroenterol Hepatol 2018; 30:1461-1469. [PMID: 30106760 DOI: 10.1097/meg.0000000000001234] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND The outcome of primary biliary cholangitis (PBC) is affected by both genetic and environmental factors. OBJECTIVE The aim of this study was to study the effect of smoking on liver histology and mortality in a genetically homogeneous population having PBC. PATIENTS AND METHODS Smoking and drinking habits at diagnosis (based on standard criteria) were recorded in 171 Cretan patients with PBC (163 women). A total of 148 patients had a liver biopsy. Odds ratios were calculated with logistic regression analysis. Kaplan-Meier curves were used for mortality estimation. RESULTS Smoking was associated with alcohol consumption of more than 20 g/day [adjusted odds ratio (AOR)=2.20, 95% CI: 1.029-4.099], severe steatosis (AOR=5.31, 95% CI: 2.019-9.919), and fibrosis stage F3-F4 (AOR=1.21, 95% CI: 1.015-3.031). Heavy smoking, years of passive smoking, and serious necroinflammatiοn were independent factors associated with advanced fibrosis after adjustment for sex, age, BMI, and alcohol consumption in multivariate analysis. For every pack-year increase in smoking intensity, there was a 3.2 times higher likelihood of advanced fibrosis (95% CI: 2.018-6.294). Increased mortality was found in smokers with advanced PBC. CONCLUSION There is an association between smoking, whether active or passive, and advanced fibrosis in PBC. Mortality is increased in smokers with advanced disease at presentation.
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Bali G, Szilvási A, Inotai D, Varga Á, Sárdy M, Kárpáti S, Medvecz M, Szegedi A, Hidvégi B. Comorbidity of localized scleroderma and primary biliary cholangitis. J Dtsch Dermatol Ges 2018; 16:1323-1327. [DOI: 10.1111/ddg.13693] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 04/28/2018] [Accepted: 05/04/2018] [Indexed: 01/13/2023]
Affiliation(s)
- Gábor Bali
- Department of Dermatology; Venereology and Dermato-Oncology; Faculty of Medicine; Semmelweis University; Budapest Hungary
| | - Anikó Szilvási
- Hungarian National Blood Transfusion Service; Transplantation Immunogenetics Laboratory; Budapest Hungary
| | - Dóra Inotai
- Hungarian National Blood Transfusion Service; Transplantation Immunogenetics Laboratory; Budapest Hungary
| | - Ágnes Varga
- Hungarian National Blood Transfusion Service; Transplantation Immunogenetics Laboratory; Budapest Hungary
| | - Miklós Sárdy
- Department of Dermatology; Venereology and Dermato-Oncology; Faculty of Medicine; Semmelweis University; Budapest Hungary
| | - Sarolta Kárpáti
- Department of Dermatology; Venereology and Dermato-Oncology; Faculty of Medicine; Semmelweis University; Budapest Hungary
| | - Márta Medvecz
- Department of Dermatology; Venereology and Dermato-Oncology; Faculty of Medicine; Semmelweis University; Budapest Hungary
| | - Anna Szegedi
- Department of Dermatology; Venereology and Dermato-Oncology; Faculty of Medicine; Semmelweis University; Budapest Hungary
| | - Bernadett Hidvégi
- Department of Dermatology; Venereology and Dermato-Oncology; Faculty of Medicine; Semmelweis University; Budapest Hungary
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Bali G, Szilvási A, Inotai D, Varga Á, Sárdy M, Kárpáti S, Medvecz M, Szegedi A, Hidvégi B. Komorbidität von lokalisierter Sklerodermie und primär biliärer Cholangitis. J Dtsch Dermatol Ges 2018; 16:1323-1328. [DOI: 10.1111/ddg.13693_g] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 05/04/2018] [Indexed: 12/28/2022]
Affiliation(s)
- Gábor Bali
- Department of Dermatology; Venereology and Dermato-Oncology; Faculty of Medicine; Semmelweis University; Budapest Hungary
| | - Anikó Szilvási
- Hungarian National Blood Transfusion Service; Transplantation Immunogenetics Laboratory; Budapest Hungary
| | - Dóra Inotai
- Hungarian National Blood Transfusion Service; Transplantation Immunogenetics Laboratory; Budapest Hungary
| | - Ágnes Varga
- Hungarian National Blood Transfusion Service; Transplantation Immunogenetics Laboratory; Budapest Hungary
| | - Miklós Sárdy
- Department of Dermatology; Venereology and Dermato-Oncology; Faculty of Medicine; Semmelweis University; Budapest Hungary
| | - Sarolta Kárpáti
- Department of Dermatology; Venereology and Dermato-Oncology; Faculty of Medicine; Semmelweis University; Budapest Hungary
| | - Márta Medvecz
- Department of Dermatology; Venereology and Dermato-Oncology; Faculty of Medicine; Semmelweis University; Budapest Hungary
| | - Anna Szegedi
- Department of Dermatology; Venereology and Dermato-Oncology; Faculty of Medicine; Semmelweis University; Budapest Hungary
| | - Bernadett Hidvégi
- Department of Dermatology; Venereology and Dermato-Oncology; Faculty of Medicine; Semmelweis University; Budapest Hungary
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48
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Hirschfield GM, Dyson JK, Alexander GJM, Chapman MH, Collier J, Hübscher S, Patanwala I, Pereira SP, Thain C, Thorburn D, Tiniakos D, Walmsley M, Webster G, Jones DEJ. The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines. Gut 2018; 67:1568-1594. [PMID: 29593060 PMCID: PMC6109281 DOI: 10.1136/gutjnl-2017-315259] [Citation(s) in RCA: 213] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 01/22/2018] [Accepted: 01/23/2018] [Indexed: 12/12/2022]
Abstract
Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disease in which a cycle of immune mediated biliary epithelial cell injury, cholestasis and progressive fibrosis can culminate over time in an end-stage biliary cirrhosis. Both genetic and environmental influences are presumed relevant to disease initiation. PBC is most prevalent in women and those over the age of 50, but a spectrum of disease is recognised in adult patients globally; male sex, younger age at onset (<45) and advanced disease at presentation are baseline predictors of poorer outcome. As the disease is increasingly diagnosed through the combination of cholestatic serum liver tests and the presence of antimitochondrial antibodies, most presenting patients are not cirrhotic and the term cholangitis is more accurate. Disease course is frequently accompanied by symptoms that can be burdensome for patients, and management of patients with PBC must address, in a life-long manner, both disease progression and symptom burden. Licensed therapies include ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), alongside experimental new and re-purposed agents. Disease management focuses on initiation of UDCA for all patients and risk stratification based on baseline and on-treatment factors, including in particular the response to treatment. Those intolerant of treatment with UDCA or those with high-risk disease as evidenced by UDCA treatment failure (frequently reflected in trial and clinical practice as an alkaline phosphatase >1.67 × upper limit of normal and/or elevated bilirubin) should be considered for second-line therapy, of which OCA is the only currently licensed National Institute for Health and Care Excellence recommended agent. Follow-up of patients is life-long and must address treatment of the disease and management of associated symptoms.
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Affiliation(s)
- Gideon M Hirschfield
- NIHR Birmingham Biomedical Research Centre, Birmingham, UK
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Jessica K Dyson
- Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
- NIHR Newcastle Biomedical Research Centre, Newcastle, United Kingdom
| | - Graeme J M Alexander
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK
| | - Michael H Chapman
- Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Jane Collier
- Translational Gastroenterology Unit, Oxford University Hospitals, University of Oxford, Oxford, UK
| | - Stefan Hübscher
- Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Imran Patanwala
- Department of Gastroenterology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK
- University of Liverpool, Liverpool, UK
| | - Stephen P Pereira
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK
- Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK
| | | | - Douglas Thorburn
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK
| | - Dina Tiniakos
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | | | - George Webster
- Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK
| | - David E J Jones
- Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
- NIHR Newcastle Biomedical Research Centre, Newcastle, United Kingdom
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49
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Tanaka A, Leung PSC, Gershwin ME. The Genetics and Epigenetics of Primary Biliary Cholangitis. Clin Liver Dis 2018; 22:443-455. [PMID: 30259846 DOI: 10.1016/j.cld.2018.03.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Both genetic background and environmental factors contribute to primary biliary cholangitis (PBC). Recent innovative technologies, such as genome-wide association studies, identified a remarkable number of susceptible nonhuman leukocyte antigen genes contributing to the development of PBC; however, they are primarily indicators of active immunologic responses commonly involved in autoimmune reactions. Thus, recent studies have focused on epigenetic mechanisms that would link genetic predisposition and environmental triggering factors. In PBC, methylation profiling and altered X chromosome architecture have been intensively explored in conjunction with a striking female predominance. Further, microRNAs have been found to be associated with the etiology of PBC.
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Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo 173-8605, Japan
| | - Patrick S C Leung
- Division of Rheumatology, Allergy and Clinical Immunology, UC Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis 95616, CA
| | - Merrill Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, UC Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis 95616, CA.
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Abstract
Primary biliary cholangitis (PBC) is considered a model autoimmune disease, characterized by circulating anti-mitochondrial antibodies and a selective autoimmune destruction of intrahepatic cholangiocytes. PBC is heterogeneous in its presentation, symptomatology, disease progression, and response to therapy. The pathogenesis is still largely unknown and epidemiologic studies have facilitated the identification of risk factors and the understanding of disease prevalence, geographic variations, heterogeneity, and differences in sex ratio. Recent studies from large international cohorts have better identified prognostic factors suggesting a change in patient management based on risk-stratification tools to identify subgroups at greatest potential benefit from second-line therapies.
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Affiliation(s)
- Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, Milan 20090, Italy; Liver Unit, Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano 20089, Milan, Italy.
| | - Francesca Colapietro
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, Milan 20090, Italy
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