Genome-wide association studies identify PRKCB as a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population

Tomohiro Tanaka; Minae Kawashima; Yuki Hitomi; Yoshihiro Aiba; Nao Nishida; Kaname Kojima; Yosuke Kawai; Hitomi Nakamura; Atsushi Tanaka; Mikio Zeniya; Etsuko Hashimoto; Hiromasa Ohira; Kazuhide Yamamoto; Masanori Abe; Kazuhiko Nakao; Satoshi Yamagiwa; Shuichi Kaneko; Masao Honda; Takeji Umemura; Takafumi Ichida; Masataka Seike; Shotaro Sakisaka; Masaru Harada; Osamu Yokosuka; Yoshiyuki Ueno; Michio Senju; Tatsuo Kanda; Hidetaka Shibata; Takashi Himoto; Kazumoto Murata; Yasuhiro Miyake; Hirotoshi Ebinuma; Makiko Taniai; Satoru Joshita; Toshiki Nikami; Hajime Ota; Hiroshi Kouno; Hirotaka Kouno; Makoto Nakamuta; Nobuyoshi Fukushima; Motoyuki Kohjima; Tatsuji Komatsu; Toshiki Komeda; Yukio Ohara; Toyokichi Muro; Tsutomu Yamashita; Kaname Yoshizawa; Yoko Nakamura; Masaaki Shimada; Noboru Hirashima; Kazuhiro Sugi; Keisuke Ario; Eiichi Takesaki; Atsushi Naganuma; Hiroshi Mano; Haruhiro Yamashita; Kouki Matsushita; Kazuhiko Yamauchi; Fujio Makita; Hideo Nishimura; Kiyoshi Furuta; Naohiro Takahashi; Masahiro Kikuchi; Naohiko Masaki; Sumito Tamura; Akira Mori; Shintaro Yagi; Ken Shirabe; Atsumasa Komori; Kiyoshi Migita; Masahiro Ito; Shinya Nagaoka; Seigo Abiru; Hiroshi Yatsuhashi; Michio Yasunami; Shinji Shimoda; Kenichi Harada; Hiroto Egawa; Yoshihiko Maehara; Shinji Uemoto; Norihiro Kokudo; Hajime Takikawa; Hiromi Ishibashi; Kazuaki Chayama; Masashi Mizokami; Masao Nagasaki; Katsushi Tokunaga; Minoru Nakamura

doi:10.1093/hmg/ddw406

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Genome-wide association studies identify PRKCB as a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population

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Genome-wide association studies identify PRKCB as a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population

Tomohiro Tanaka, Minae Kawashima, Yuki Hitomi, Yoshihiro Aiba, Nao Nishida, Kaname Kojima, Yosuke Kawai, Hitomi Nakamura, Atsushi Tanaka, Mikio Zeniya, …

Human molecular genetics, Vol.26(3), pp.650-659

02/01/2017

DOI: 10.1093/hmg/ddw406

PMID: 28062665

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Abstract

A previous genome-wide association study (GWAS) performed in 963 Japanese individuals (487 primary biliary cholangitis [PBC] cases and 476 healthy controls) identified TNFSF15 (rs4979462) and POU2AF1 (rs4938534) as strong susceptibility loci for PBC. In this study, we performed GWAS in additional 1,923 Japanese individuals (894 PBC cases and 1,029 healthy controls), and combined the results with the previous data. This GWAS, together with a subsequent replication study in an independent set of 7,024 Japanese individuals (512 PBC cases and 6,512 healthy controls), identified PRKCB (rs7404928) as a novel susceptibility locus for PBC (odds ratio [OR] = 1.26, P = 4.13 × 10-9). Furthermore, a primary functional variant of PRKCB (rs35015313) was identified by genotype imputation using a phased panel of 1,070 Japanese individuals from a prospective, general population cohort study and subsequent in vitro functional analyses. These results may lead to improved understanding of the disease pathways involved in PBC, forming a basis for prevention of PBC and development of novel therapeutics.

Japan

Asian Continental Ancestry Group

Genetic Predisposition to Disease

Genome-Wide Association Study

Humans

Protein Kinase C beta - genetics

Female

Genotype

Male

Polymorphism, Single Nucleotide

Liver Cirrhosis, Biliary - pathology

Liver Cirrhosis, Biliary - genetics

Details

Title: Subtitle: Genome-wide association studies identify PRKCB as a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population
Creators: Tomohiro Tanaka - Organ Transplantation Service, The University of Tokyo, Tokyo, Japan
Minae Kawashima - Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Yuki Hitomi - Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Yoshihiro Aiba - Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan
Nao Nishida - The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
Kaname Kojima - Division of Biomedical Information Analysis, Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
Yosuke Kawai - Division of Biomedical Information Analysis, Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
Hitomi Nakamura - Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan
Atsushi Tanaka - Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
Mikio Zeniya - Department of Gastroenterology and Hepatology, Tokyo Jikei University School of Medicine, Tokyo, Japan
Etsuko Hashimoto - Department of Medicine and Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
Hiromasa Ohira - Department of Gastroenterology and Rheumatic Diseases, Fukushima Medical University of Medicine, Fukushima, Japan
Kazuhide Yamamoto - Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Masanori Abe - Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Japan
Kazuhiko Nakao - Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagaski, Japan
Satoshi Yamagiwa - Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 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
Takeji Umemura - Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
Takafumi Ichida - Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka, Japan
Masataka Seike - First Department of Internal Medicine, Faculty of Medicine, Oita University, Oita, Japan
Shotaro Sakisaka - 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
Osamu Yokosuka - 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
Michio Senju - The Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
Tatsuo Kanda - Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
Hidetaka Shibata - Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagaski, 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
Yasuhiro Miyake - Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Hirotoshi Ebinuma - Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio Graduate School of Medicine, Tokyo, Japan
Makiko Taniai - Department of Medicine and Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
Satoru Joshita - Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
Toshiki Nikami - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Hajime Ota - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Hiroshi Kouno - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Hirotaka Kouno - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Makoto Nakamuta - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Nobuyoshi Fukushima - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Motoyuki Kohjima - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Tatsuji Komatsu - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Toshiki Komeda - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Yukio Ohara - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Toyokichi Muro - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Tsutomu Yamashita - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Kaname Yoshizawa - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Yoko Nakamura - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Masaaki Shimada - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Noboru Hirashima - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Kazuhiro Sugi - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Keisuke Ario - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Eiichi Takesaki - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Atsushi Naganuma - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Hiroshi Mano - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Haruhiro Yamashita - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Kouki Matsushita - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Kazuhiko Yamauchi - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Fujio Makita - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Hideo Nishimura - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Kiyoshi Furuta - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Naohiro Takahashi - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Masahiro Kikuchi - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Naohiko Masaki - Headquaters of PBC Research in the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Sumito Tamura - Hepatobiliarypancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Akira Mori - Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Shintaro Yagi - Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Ken Shirabe - Department of Surgery and Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
Atsumasa Komori - Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan
Kiyoshi Migita - Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan
Masahiro Ito - Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, 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
Hiroshi Yatsuhashi - Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan
Michio Yasunami - Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan
Shinji Shimoda - Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
Kenichi Harada - Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
Hiroto Egawa - Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, 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 - Hepatobiliarypancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Hajime Takikawa - Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
Hiromi Ishibashi - Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan
Kazuaki Chayama - Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
Masashi Mizokami - The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
Masao Nagasaki - Division of Biomedical Information Analysis, Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
Katsushi Tokunaga - Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Minoru Nakamura - Headquaters of gp210 Working Group in Intractable Liver Disease Research Project Team of the Ministry of Health and Welfare in Japan, Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.26(3), pp.650-659
DOI: 10.1093/hmg/ddw406
PMID: 28062665
ISSN: 0964-6906
eISSN: 1460-2083
Language: English
Date published: 02/01/2017
Academic Unit: Gastroenterology and Hepatology; Internal Medicine
Record Identifier: 9984094558102771

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