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

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7 Citations (Scopus)


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
Issue number1
Publication statusPublished - Dec 1 2018

All Science Journal Classification (ASJC) codes

  • General


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