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Sci Rep. 2018 May 23;8(1):8071. doi: 10.1038/s41598-018-26369-6.

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

Author information

1
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
2
Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Japan.
3
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan.
4
Division of Biomedical Information Analysis, Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
5
Organ Transplantation Service, The University of Tokyo, Tokyo, Japan.
6
Hepatobiliarypancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
7
Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
8
Department of Surgery and Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
9
Department of Transplantation and Digestive Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
10
Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan.
11
Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
12
Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
13
Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan.
14
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan. nakamuram@nagasaki-mc.com.
15
Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan. nakamuram@nagasaki-mc.com.
16
Headquarters of PBC-GWAS Consortium in Japan (PBCJPN), National Hospital Organization (NHO) Study Group for Liver Disease in Japan (NHOSLJ), and gp210 Working Group in Intractable Liver Disease Research Project Team of the Ministry of Health and Welfare in Japan, Omura, Japan. nakamuram@nagasaki-mc.com.

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.

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