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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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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. |
format | Online Article Text |
id | pubmed-5966418 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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