Abstract
Approximately 10-20% of patients with primary biliary cholangitis (PBC) progress to jaundice stage regardless of treatment with ursodeoxycholic acid and bezafibrate. In this study, we performed a GWAS and a replication study to identify genetic variants associated with jaundice-stage progression in PBC using a total of 1,375 patients (1,202 early-stage and 173 jaundice-stage) in a Japanese population. SNP rs13720, which is located in the 3′UTR of cathepsin Z (CTSZ), showed the strongest association (odds ratio [OR] = 2.15, P = 7.62 × 10-7) with progression to jaundice stage in GWAS. High-density association mapping at the CTSZ and negative elongation factor complex member C/D (NELFCD) loci, which are located within a strong linkage disequilibrium (LD) block, revealed that an intronic SNP of CTSZ, rs163800, was significantly associated with jaundice-stage progression (OR = 2.16, P = 8.57 × 10-8). In addition, eQTL analysis and in silico functional analysis indicated that genotypes of rs163800 or variants in strong LD with rs163800 influence expression levels of both NELFCD and CTSZ mRNA. The present novel findings will contribute to dissect the mechanism of PBC progression and also to facilitate the development of therapies for PBC patients who are resistant to current therapies.
| Original language | English |
|---|---|
| Article number | 8071 |
| Journal | Scientific Reports |
| Volume | 8 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2018 Dec 1 |
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In: Scientific Reports, Vol. 8, No. 1, 8071, 01.12.2018.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese population
AU - Nishida, Nao
AU - Aiba, Yoshihiro
AU - Hitomi, Yuki
AU - Kawashima, Minae
AU - Kojima, Kaname
AU - Kawai, Yosuke
AU - Ueno, Kazuko
AU - Nakamura, Hitomi
AU - Yamashiki, Noriyo
AU - Tanaka, Tomohiro
AU - Tamura, Sumito
AU - Mori, Akira
AU - Yagi, Shintaro
AU - Soejima, Yuji
AU - Yoshizumi, Tomoharu
AU - Takatsuki, Mitsuhisa
AU - Tanaka, Atsushi
AU - Harada, Kenichi
AU - Shimoda, Shinji
AU - Komori, Atsumasa
AU - Eguchi, Susumu
AU - Maehara, Yoshihiko
AU - Uemoto, Shinji
AU - Kokudo, Norihiro
AU - Nagasaki, Masao
AU - Tokunaga, Katsushi
AU - Nakamura, Minoru
N1 - Funding Information: This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (#23591006, #26293181) to Minoru Nakamura, Yoshihiro Aiba (#15K19357, #17K09449), Yuki Hitomi (#15K19314), and Minae Kawashima (#15K06908); a Grant-in-Aid for Clinical Research from the National Hospital Organization to Minoru Nakamura; a grant from the Research Program for Intractable Disease, provided by the Ministry of Health, Labour and Welfare of Japan to Minoru Nakamura; Grants-in-Aid from the Ministry of Health, Labour and Welfare of Japan to Katsushi Tokunaga (H26-kanenjitsu-kanen-ippan-004) and the Japan Agency for Medical Research and Development to Katsushi Tokunaga, Masao Nagasaki, Yosuke Kawai, Kaname Kojima, and Yuki Hitomi (Platform Program for Promotion of Genome Medicine, 16 km0405205h0101); and grants from The Uehara Memorial Foundation, Takeda Science Foundation, and Senshin Medical Research Foundation to Yuki Hitomi. Funding Information: We are indebted to all volunteers who participated in our PBC project. We also thank Drs Toshiki Nikami, Hajime Ota, Hiroshi Kouno, Hirotaka Kouno, Makoto Nakamuta, Nobuyoshi Fukushima, Tatsuji Komatsu, Toshiki Komeda, Shinji Katsushima, Yukio Ohara, Seiji Tsunematsu, Toyokichi Muro, Tsutomu Yamashita, Kaname Yoshizawa, Yoko Nakamura, Masaaki Shimada, Noboru Hirashima, Kazuhiro Sugi, Keisuke Ario, Eiichi Takesaki, Noriaki Naeshiro, Atsushi Naganuma, Hiroshi Mano, Haruhiro Yamashita, Kouki Matsushita, Fujio Makita, Hideo Nishimura, Kiyoshi Furuta, Naohiro Takahashi, Masahiro Kikuchi, Naohiko Masaki, Hitoshi Takaki, Takeaki Sato, Masahiko Takahashi, Tetsuo Yamamoto, Masaharu Koda, Hironori Sakai, Michio Kato, Iwao Yabuuchi, Yuko Nagaoki, Noriaki Naeshiro, Shigeki Hayashi, Koichi Honda, Jinya Ishida, Yukio Watanabe, Masakazu Kobayashi, Michiaki Koga, Takeo Saoshiro, Michiyasu Yagura, Yuji Kamitsukasa, Keisuke Hirata, Yusuke Shimada, Eiji Mita, Kazuhiko Yamauchi, Rie Sugimoto (Members of PBC Research in the NHO Study Group for Liver Disease in Japan (NHOSLJ)), 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 University, Tokyo, Japan), Hiromasa Ohira (Department of Gastroenterology and Rheumatic Diseases, Fukushima Medical University of Medicine, Fukushima, Japan), Takeji Umemura Satoru Joshita (Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan), Kazuhide Yamamoto, Akinobu Takaki (Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan), Masanori Abe, Morikazu Onji (Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Japan), Kazuhiko Nakao, Tatsuki Ichikawa, Hidetaka Shibata (Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan), Satoshi Yamagiwa (Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan), Shuichi Kaneko, Masao Honda, Kuniaki Arai (Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan), Takafumi Ichida, Katsuji Hirano (Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka, Japan), Masataka Seike (Faculty of Medicine, Oita University, Oita, Japan), Shotaro Sakisaka, Yasuaki Takeyama (Department of Gastroenterology and Medicine, Fukuoka, University School of Medicine, Fukuoka, Japan), Masaru Harada, Michio Senju (The Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan), Osamu Yokosuka, 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), Yasuhiko Sugawara, Kiyoshi Hasegawa (Hepatobiliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan), Ken Shirabe, Akinobu Taketomi (Department of Surgery and Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan), Kiyoshi Migita, Masahiro Ito, Shinya Nagaoka, Seigo Abiru, and Hiroshi Yatsuhashi (Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan), for collecting clinical data and blood samples, and for obtaining informed consent from PBC cases. We are also grateful to Mayumi Ishii, Takayo Tsuchiura (National Center for Global Health and Medicine), Dr. Hiromi Sawai, Megumi Sageshima, Yuko Hirano, Natsumi Baba, Rieko Shirahashi, and Ayumi Ogawa (The University of Tokyo) for technical assistance. This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (#23591006, #26293181) to Minoru Nakamura, Yoshihiro Aiba (#15K19357, #17K09449), Yuki Hitomi (#15K19314), and Minae Kawashima (#15K06908); a Grant-in-Aid for Clinical Research from the National Hospital Organization to Minoru Nakamura; a grant from the Research Program for Intractable Disease, provided by the Ministry of Health, Labour and Welfare of Japan to Minoru Nakamura; Grants-in-Aid from the Ministry of Health, Labour and Welfare of Japan to Katsushi Tokunaga (H26-kanenjitsu-kanen-ippan-004) and the Japan Agency for Medical Research and Development to Katsushi Tokunaga, Masao Nagasaki, Yosuke Kawai, Kaname Kojima, and Yuki Hitomi (Platform Program for Promotion of Genome Medicine, 16 km0405205h0101); and grants from The Uehara Memorial Foundation, Takeda Science Foundation, and Senshin Medical Research Foundation to Yuki Hitomi. Publisher Copyright: © 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Approximately 10-20% of patients with primary biliary cholangitis (PBC) progress to jaundice stage regardless of treatment with ursodeoxycholic acid and bezafibrate. In this study, we performed a GWAS and a replication study to identify genetic variants associated with jaundice-stage progression in PBC using a total of 1,375 patients (1,202 early-stage and 173 jaundice-stage) in a Japanese population. SNP rs13720, which is located in the 3′UTR of cathepsin Z (CTSZ), showed the strongest association (odds ratio [OR] = 2.15, P = 7.62 × 10-7) with progression to jaundice stage in GWAS. High-density association mapping at the CTSZ and negative elongation factor complex member C/D (NELFCD) loci, which are located within a strong linkage disequilibrium (LD) block, revealed that an intronic SNP of CTSZ, rs163800, was significantly associated with jaundice-stage progression (OR = 2.16, P = 8.57 × 10-8). In addition, eQTL analysis and in silico functional analysis indicated that genotypes of rs163800 or variants in strong LD with rs163800 influence expression levels of both NELFCD and CTSZ mRNA. The present novel findings will contribute to dissect the mechanism of PBC progression and also to facilitate the development of therapies for PBC patients who are resistant to current therapies.
AB - Approximately 10-20% of patients with primary biliary cholangitis (PBC) progress to jaundice stage regardless of treatment with ursodeoxycholic acid and bezafibrate. In this study, we performed a GWAS and a replication study to identify genetic variants associated with jaundice-stage progression in PBC using a total of 1,375 patients (1,202 early-stage and 173 jaundice-stage) in a Japanese population. SNP rs13720, which is located in the 3′UTR of cathepsin Z (CTSZ), showed the strongest association (odds ratio [OR] = 2.15, P = 7.62 × 10-7) with progression to jaundice stage in GWAS. High-density association mapping at the CTSZ and negative elongation factor complex member C/D (NELFCD) loci, which are located within a strong linkage disequilibrium (LD) block, revealed that an intronic SNP of CTSZ, rs163800, was significantly associated with jaundice-stage progression (OR = 2.16, P = 8.57 × 10-8). In addition, eQTL analysis and in silico functional analysis indicated that genotypes of rs163800 or variants in strong LD with rs163800 influence expression levels of both NELFCD and CTSZ mRNA. The present novel findings will contribute to dissect the mechanism of PBC progression and also to facilitate the development of therapies for PBC patients who are resistant to current therapies.
UR - http://www.scopus.com/inward/record.url?scp=85047561862&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047561862&partnerID=8YFLogxK
U2 - 10.1038/s41598-018-26369-6
DO - 10.1038/s41598-018-26369-6
M3 - Article
C2 - 29795304
AN - SCOPUS:85047561862
SN - 2045-2322
VL - 8
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 8071
ER -