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

Nao Nishida, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Kaname Kojima, Yosuke Kawai, Kazuko Ueno, Hitomi Nakamura, Noriyo Yamashiki, Tomohiro Tanaka, Sumito Tamura, Akira Mori, Shintaro Yagi, Yuji Soejima, Tomoharu Yoshizumi, Mitsuhisa Takatsuki, Atsushi Tanaka, Kenichi Harada, Shinji Shimoda, Atsumasa KomoriSusumu Eguchi, Yoshihiko Maehara, Shinji Uemoto, Norihiro Kokudo, Masao Nagasaki, Katsushi Tokunaga, Minoru Nakamura

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 languageEnglish
Article number8071
JournalScientific reports
Volume8
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

Fingerprint

Cathepsin Z
Cholangitis
Jaundice
Population
Genome-Wide Association Study
Linkage Disequilibrium
Single Nucleotide Polymorphism
Odds Ratio
Bezafibrate
Ursodeoxycholic Acid
Computer Simulation
Therapeutics
Genotype
negative elongation factor
Messenger RNA

All Science Journal Classification (ASJC) codes

  • General

Cite this

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.

In: Scientific reports, Vol. 8, No. 1, 8071, 01.12.2018.

Research output: Contribution to journalArticle

Nishida, N, Aiba, Y, Hitomi, Y, Kawashima, M, Kojima, K, Kawai, Y, Ueno, K, Nakamura, H, Yamashiki, N, Tanaka, T, Tamura, S, Mori, A, Yagi, S, Soejima, Y, Yoshizumi, T, Takatsuki, M, Tanaka, A, Harada, K, Shimoda, S, Komori, A, Eguchi, S, Maehara, Y, Uemoto, S, Kokudo, N, Nagasaki, M, Tokunaga, K & Nakamura, M 2018, 'NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese population', Scientific reports, vol. 8, no. 1, 8071. https://doi.org/10.1038/s41598-018-26369-6
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. In: Scientific reports. 2018 ; Vol. 8, No. 1.
@article{b92f6469e43c4e468a63f5ced9822cfd,
title = "NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese population",
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.",
author = "Nao Nishida and Yoshihiro Aiba and Yuki Hitomi and Minae Kawashima and Kaname Kojima and Yosuke Kawai and Kazuko Ueno and Hitomi Nakamura and Noriyo Yamashiki and Tomohiro Tanaka and Sumito Tamura and Akira Mori and Shintaro Yagi and Yuji Soejima and Tomoharu Yoshizumi and Mitsuhisa Takatsuki and Atsushi Tanaka and Kenichi Harada and Shinji Shimoda and Atsumasa Komori and Susumu Eguchi and Yoshihiko Maehara and Shinji Uemoto and Norihiro Kokudo and Masao Nagasaki and Katsushi Tokunaga and Minoru Nakamura",
year = "2018",
month = "12",
day = "1",
doi = "10.1038/s41598-018-26369-6",
language = "English",
volume = "8",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

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

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

AN - SCOPUS:85047561862

VL - 8

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 8071

ER -