Disease susceptibility genes shared by primary biliary cirrhosis and Crohn’s disease in the Japanese population

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We previously identified TNFSF15 as the most significant susceptibility gene at non-HLA loci for both primary biliary cirrhosis (PBC) and Crohn’s diseases (CD) in the Japanese population. The aim of this study is to identify further disease susceptibility genes shared by PBC and CD. We selected 15 and 33 genetic variants that were significantly associated with PBC and CD, respectively, based on previously reported genome-wide association studies of the Japanese population. Next, an association study was independently performed for these genetic variants in CD (1312 CD patients and 3331 healthy controls) and PBC (1279 PBC patients and 1015 healthy controls) cohorts. Two CD susceptibility genes, ICOSLG rs2838519 and IL12B rs6556412, were also nominally associated with susceptibility to PBC (P=3.85 × 10−2 and P=8.40 × 10−3, respectively). Three PBC susceptibility genes, CXCR5 rs6421571, STAT4 rs7574865 and NFKB1 rs230534, were nominally associated with susceptibility to CD (P=2.82 × 10−2, P=3.88 × 10−2 and P=2.04 × 10−2, respectively). The effect of ICOSLG and CXCR5 variants were concordant but the effect of STAT4, NFKB1 and IL12B variants were discordant for PBC and CD. TNFSF15 and ICOSLG-CXCR5 might constitute a shared pathogenic pathway in the development of PBC and CD in the Japanese population, whereas IL12B-STAT4-NFKB1 might constitute an opposite pathogenic pathway, reflecting the different balance between Th1 and Th17 in the two diseases.

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We thank the PBC patients and healthy volunteers for participating in this study, as well as the following members for obtaining informed consent and collecting serum and DNA samples from PBC patients: PBC Study Group of NHSOLJ; Drs. Hiromi Ishibashi, Hiroshi Yatsuhashi, Seigo Abiru, Shinya Nagaoka (NHO Nagasaki Medical Center), Makoto Nakamuta, Motoyuki Kohjima (NHO Kyushu Medical Center), Hajime Ota (NHO Kanazawa Medical Center), Tatsuji Komatsu (NHO Yokohama Medical Center), Toshiki Nikami, Jinya Ishida, Takeo Saoshiro (NHO Nishisaitama Hospital), Hirotsugu Kouno, Hirotaka Kouno (NHO Kure Medical Center), Hiroshi Kamitsukasa (NHO Tokyo Hospital), Kiyoshi Furuta (NHO Matsumoto Medical Center), Toyokichi Muro, Tsutomu Yamashita (NHO Oita Medical Center), Naohiko Masaki (National Center for Global Health and Medicine), Yusuke Shimada (NHO National Disaster Medical Center), Yukio Watanabe, Yoko Nakamura (NHO Sagamihara Hospital), Masaaki Shimada, Noboru Hirashima (NHO Nagoya Medical Center), Toshiki Komeda (NHO Kyoto Medical Center), Kazuhiro Sugi (NHO Kumamoto Medical Center), Eiichi Takesaki, Yuko Nagaoki (NHO Higashi-Hiroshima Medical Center), Yukio Ohara (NHO Hokkaido Medical Center), Hiroshi Mano (NHO Sendai Medical Center), Haruhiro Yamashita, Kouki Matsushita (NHO Okayama Medical Center), Keisuke Ario (NHO Ureshino Medical Center), Masahiko Takahashi (NHO Tokyo Medical Center), Tetsuo Yamamoto (NHO Yonago Medical Center), Fujio Makita (NHO Nishigunma Hospital), Hideo Nishimura (NHO Asahikawa Medical Center), Hitoshi Takagi, Atsushi Naganuma (NHO Takasaki General Medical Center) and Kaname Yoshizawa (NHO Shinshu Ueda Medical Center), Eiji Mita (NHO Osaka Medical Center); gp210 working in Research Program of Intractable Hepatoboliary Disease Study Group supported by the Ministry of Health, Labour and Welfare of Japan: Drs. Atsushi Tanaka, Hajime Takikawa (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, Makiko Taniai (Department of Medicine and Gastroenterology, Tokyo Women's Medical Universiy, Tokyo, Japan), Hiromasa Ohira (Department of Gastroenterology and Rheumatic Diseases, Fukushima Medical University of Medicine, Fukushima, Japan), Kazuhide Yamamoto, Yasuhiro Miyake (Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan), Morikazu Onji, Masanori Abe (Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Japan), Shuichi Kaneko, Masao Honda, Kuniaki Arai (Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan), Satoshi Yamagiwa (Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan), Kazuhiko Nakao, Hidetaka Shibata (Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagaski, 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), Takeji Umemura, Satoru Joshita (Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan), Yoshiyuki Ueno (Department of Gastroenterology,Yamagata University Faculty of Medicine,Yamagata, Japan), Shotaro Sakisaka, Yasuaki Takeyama (Department of Gastroenterology and Medicine, Fukuoka University School of Medicine, Fukuoka, Japan), Shinji Shimoda (Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan), Kentaro Kikuchi (Deprtment of Internal Medicine, Teikyo University Mizonokuchi Hospital, Kawasaki, Japan), Hirotoshi Ebinuma (Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio Graduate School of Medicine, Tokyo, Japan), Tatsuo Kanda, Osamu Yokosuga (Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan), Takashi Himoto (Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Kagawa, Japan),Toshio Senju, Masaru Harada (Third Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan), Kazumoto Murata, Masashi Mizokami (The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan), Ken Shirabe, Yoshihiko Maehara (Department of Surgery and Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan), Noriyo Yamashiki, Tomohiro Tanaka (Organ Transplantation Service, The University of Tokyo, Tokyo, Japan), Sumito Tamura, Yasuhiko Sugawara, Norihiro Kokudo (Hepatobiliary- pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan), Akira Mori, Michiyasu Yagi, Shinji Uemoto (Division of Hepato-Biliary- Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan), Hirohito Tsubouchi (Department of Digestive and Life-style related Disease, Kagoshima University Graduate School of Medical and Dental Science, Kagoshima, Japan). This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science to MN (#26293181, #23591006), KY (#26293180) and YA (#25860576); by a Grant-in Aid for Clinical Research from the National Hospital Organization to MN; and by a Grant from the Research Program of Intractable Disease provided by the Ministry of Health, Labour and Welfare of Japan to MN. This work was supported in part by the Biobank Japan project funded by the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Correspondence to Minoru Nakamura.

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