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NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese population

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...

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Autores principales: Nishida, Nao, Aiba, Yoshihiro, Hitomi, Yuki, Kawashima, Minae, Kojima, Kaname, Kawai, Yosuke, Ueno, Kazuko, Nakamura, Hitomi, Yamashiki, Noriyo, Tanaka, Tomohiro, Tamura, Sumito, Mori, Akira, Yagi, Shintaro, Soejima, Yuji, Yoshizumi, Tomoharu, Takatsuki, Mitsuhisa, Tanaka, Atsushi, Harada, Kenichi, Shimoda, Shinji, Komori, Atsumasa, Eguchi, Susumu, Maehara, Yoshihiko, Uemoto, Shinji, Kokudo, Norihiro, Nagasaki, Masao, Tokunaga, Katsushi, Nakamura, Minoru
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966418/
https://www.ncbi.nlm.nih.gov/pubmed/29795304
http://dx.doi.org/10.1038/s41598-018-26369-6
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author Nishida, Nao
Aiba, Yoshihiro
Hitomi, Yuki
Kawashima, Minae
Kojima, Kaname
Kawai, Yosuke
Ueno, Kazuko
Nakamura, Hitomi
Yamashiki, Noriyo
Tanaka, Tomohiro
Tamura, Sumito
Mori, Akira
Yagi, Shintaro
Soejima, Yuji
Yoshizumi, Tomoharu
Takatsuki, Mitsuhisa
Tanaka, Atsushi
Harada, Kenichi
Shimoda, Shinji
Komori, Atsumasa
Eguchi, Susumu
Maehara, Yoshihiko
Uemoto, Shinji
Kokudo, Norihiro
Nagasaki, Masao
Tokunaga, Katsushi
Nakamura, Minoru
author_facet Nishida, Nao
Aiba, Yoshihiro
Hitomi, Yuki
Kawashima, Minae
Kojima, Kaname
Kawai, Yosuke
Ueno, Kazuko
Nakamura, Hitomi
Yamashiki, Noriyo
Tanaka, Tomohiro
Tamura, Sumito
Mori, Akira
Yagi, Shintaro
Soejima, Yuji
Yoshizumi, Tomoharu
Takatsuki, Mitsuhisa
Tanaka, Atsushi
Harada, Kenichi
Shimoda, Shinji
Komori, Atsumasa
Eguchi, Susumu
Maehara, Yoshihiko
Uemoto, Shinji
Kokudo, Norihiro
Nagasaki, Masao
Tokunaga, Katsushi
Nakamura, Minoru
author_sort Nishida, Nao
collection PubMed
description 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.
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spelling pubmed-59664182018-05-24 NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese population Nishida, Nao Aiba, Yoshihiro Hitomi, Yuki Kawashima, Minae Kojima, Kaname Kawai, Yosuke Ueno, Kazuko Nakamura, Hitomi Yamashiki, Noriyo Tanaka, Tomohiro Tamura, Sumito Mori, Akira Yagi, Shintaro Soejima, Yuji Yoshizumi, Tomoharu Takatsuki, Mitsuhisa Tanaka, Atsushi Harada, Kenichi Shimoda, Shinji Komori, Atsumasa Eguchi, Susumu Maehara, Yoshihiko Uemoto, Shinji Kokudo, Norihiro Nagasaki, Masao Tokunaga, Katsushi Nakamura, Minoru Sci Rep Article 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. Nature Publishing Group UK 2018-05-23 /pmc/articles/PMC5966418/ /pubmed/29795304 http://dx.doi.org/10.1038/s41598-018-26369-6 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Nishida, Nao
Aiba, Yoshihiro
Hitomi, Yuki
Kawashima, Minae
Kojima, Kaname
Kawai, Yosuke
Ueno, Kazuko
Nakamura, Hitomi
Yamashiki, Noriyo
Tanaka, Tomohiro
Tamura, Sumito
Mori, Akira
Yagi, Shintaro
Soejima, Yuji
Yoshizumi, Tomoharu
Takatsuki, Mitsuhisa
Tanaka, Atsushi
Harada, Kenichi
Shimoda, Shinji
Komori, Atsumasa
Eguchi, Susumu
Maehara, Yoshihiko
Uemoto, Shinji
Kokudo, Norihiro
Nagasaki, Masao
Tokunaga, Katsushi
Nakamura, Minoru
NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese population
title NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese population
title_full NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese population
title_fullStr NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese population
title_full_unstemmed NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese population
title_short NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese population
title_sort nelfcd and ctsz loci are associated with jaundice-stage progression in primary biliary cholangitis in the japanese population
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966418/
https://www.ncbi.nlm.nih.gov/pubmed/29795304
http://dx.doi.org/10.1038/s41598-018-26369-6
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