Dataset Information

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.

SUBMITTER: Nishida N

PROVIDER: S-EPMC5966418 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

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

Scientific reports 20180523 1

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 associat ...[more]

PMID: 29795304

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Project description:Purpose of reviewPrimary biliary cholangitis (PBC) is characterized by autoimmune damage of intrahepatic bile ducts associated with a loss of tolerance to mitochondrial antigens. PBC etiopathogenesis is intriguing because of different perplexing features, namely: a) although mitochondria are present in all cell types and tissues, the damage is mainly restricted to biliary epithelial cells (BECs); b) despite being an autoimmune disorder, it does not respond to immunosuppressive drugs but rather to ursodeoxycholic acid, a bile salt that induces HCO3- rich choleresis; c) the overwhelming female preponderance of the disease remains unexplained. Here we present an etiopathogenic view of PBC which sheds light on these puzzling facts of the disease.Recent findingsPBC develops in patients with genetic predisposition to autoimmunity in whom epigenetic mechanisms silence the Cl-/HCO3- exchanger AE2 in both cholangiocytes and lymphoid cells. Defective AE2 function can produce BECs damage as a result of decreased biliary HCO3- secretion with disruption of the protective alkaline umbrella that normally prevents the penetration of toxic apolar bile salts into cholangiocytes. AE2 dysfunction also causes increased intracellular pH (pHi) in cholangiocytes, leading to the activation of soluble adenylyl cyclase, which sensitizes BECs to bile salt-induced apoptosis. Recently, mitophagy was found to be inhibited by cytosolic alkalization and stimulated by acidification. Accordingly, we propose that AE2 deficiency may disturb mitophagy in BECs, thus, promoting the accumulation of defective mitochondria, oxidative stress and presentation of mitochondrial antigens to the immune cells. As women possess a more acidic endolysosomal milieu than men, mitophagy might be more affected in women in an AE2-defective background. Apart from affecting BECs function, AE2 downregulation in lymphocytes may also contribute to alter immunoregulation facilitating autoreactive T-cell responses.SummaryPBC can be considered as a disorder of Cl-/HCO3- exchange in individuals with genetic predisposition to autoimmunity.

Dataset Information

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

Publications

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

Similar Datasets

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