Author information

¹Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.

²Genome Medical Science Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.

³Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan.

⁴The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.

⁵Department of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.

⁶Laboratory for Human Immunogenetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

⁷Division of Biomedical Information Analysis, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.

⁸Japan Science and Technology Agency (JST), Tokyo, Japan.

⁹Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore, Singapore.

¹⁰Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan.

¹¹Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan.

¹²Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

¹³Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.

¹⁴Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.

¹⁵Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Japan.

¹⁶The Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

¹⁷Department of Medicine and Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.

¹⁸Department of Gastroenterology and Hepatology, Tokyo Jikei University School of Medicine, Tokyo, Japan.

¹⁹Department of Gastroenterology and Rheumatic Diseases, Fukushima Medical University of Medicine, Fukushima, Japan.

²⁰Division of Gastroenterology and Hepatology, Third Department of Internal Medicine, Kansai Medical University, Hirakata, Japan.

²¹Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan.

²²Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan.

²³Human Biosciences Unit for the Top Global Course Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan.

Abstract

Background aims: Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-non-specific) and non-shared (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 results: Protein tyrosine phosphatase non-receptor type 2 (PTPN2) was identified as a novel PBC susceptibility gene locus through a GWAS and subsequent genome-wide meta-analysis involving 2,181 cases and 2,699 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 (Tfh) and plasmacytoid dendritic cells (pDCs). Infiltration of PTPN2-positive T-cells and pDCs were 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 via an insufficient negative feedback loop caused by the PTPN2 risk allele of rs2292758 in IFNg signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment.