Dataset Information

POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33.

ABSTRACT: Primary biliary cholangitis (PBC) is a chronic and cholestatic autoimmune liver disease caused by the destruction of intrahepatic small bile ducts. Our previous genome-wide association study (GWAS) identified six susceptibility loci for PBC. Here, in order to further elucidate the genetic architecture of PBC, a GWAS was performed on an additional independent sample set, then a genome-wide meta-analysis with our previous GWAS was performed based on a whole-genome single nucleotide polymorphism (SNP) imputation analysis of a total of 4,045 Japanese individuals (2,060 cases and 1,985 healthy controls). A susceptibility locus on chromosome 3q13.33 (including ARHGAP31, TMEM39A, POGLUT1, TIMMDC1, and CD80) was previously identified both in the European and Chinese populations and was replicated in the Japanese population (OR?=?0.7241, P?=?3.5?×?10-9). Subsequent in silico and in vitro functional analyses identified rs2293370, previously reported as the top-hit SNP in this locus in the European population, as the primary functional SNP. Moreover, e-QTL analysis indicated that the effector gene of rs2293370 was Protein O-Glucosyltransferase 1 (POGLUT1) (P?=?3.4?×?10-8). This is the first study to demonstrate that POGLUT1 and not CD80 is the effector gene regulated by the primary functional SNP rs2293370, and that increased expression of POGLUT1 might be involved in the pathogenesis of PBC.

SUBMITTER: Hitomi Y

PROVIDER: S-EPMC6331557 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33.

Hitomi Yuki Y Ueno Kazuko K Kawai Yosuke Y Nishida Nao N Kojima Kaname K Kawashima Minae M Aiba Yoshihiro Y Nakamura Hitomi H Kouno Hiroshi H Kouno Hirotaka H Ohta Hajime H Sugi Kazuhiro K Nikami Toshiki T Yamashita Tsutomu T Katsushima Shinji S Komeda Toshiki T Ario Keisuke K Naganuma Atsushi A Shimada Masaaki M Hirashima Noboru N Yoshizawa Kaname K Makita Fujio F Furuta Kiyoshi K Kikuchi Masahiro M Naeshiro Noriaki N Takahashi Hironao H Mano Yutaka Y Yamashita Haruhiro H Matsushita Kouki K Tsunematsu Seiji S Yabuuchi Iwao I Nishimura Hideo H Shimada Yusuke Y Yamauchi Kazuhiko K Komatsu Tatsuji T Sugimoto Rie R Sakai Hironori H Mita Eiji E Koda Masaharu M Nakamura Yoko Y Kamitsukasa Hiroshi H Sato Takeaki T Nakamuta Makoto M Masaki Naohiko N Takikawa Hajime H Tanaka Atsushi A Ohira Hiromasa H Zeniya Mikio M Abe Masanori M Kaneko Shuichi S Honda Masao M Arai Kuniaki K Arinaga-Hino Teruko T Hashimoto Etsuko E Taniai Makiko M Umemura Takeji T Joshita Satoru S Nakao Kazuhiko K Ichikawa Tatsuki T Shibata Hidetaka H Takaki Akinobu A Yamagiwa Satoshi S Seike Masataka M Sakisaka Shotaro S Takeyama Yasuaki Y Harada Masaru M Senju Michio M Yokosuka Osamu O Kanda Tatsuo T Kanda Tatsuo T Ueno Yoshiyuki Y Ebinuma Hirotoshi H Himoto Takashi T Murata Kazumoto K Shimoda Shinji S Nagaoka Shinya S Abiru Seigo S Komori Atsumasa A Migita Kiyoshi K Ito Masahiro M Yatsuhashi Hiroshi H Maehara Yoshihiko Y Uemoto Shinji S Kokudo Norihiro N Nagasaki Masao M Tokunaga Katsushi K Nakamura Minoru M

Scientific reports 20190114 1

Primary biliary cholangitis (PBC) is a chronic and cholestatic autoimmune liver disease caused by the destruction of intrahepatic small bile ducts. Our previous genome-wide association study (GWAS) identified six susceptibility loci for PBC. Here, in order to further elucidate the genetic architecture of PBC, a GWAS was performed on an additional independent sample set, then a genome-wide meta-analysis with our previous GWAS was performed based on a whole-genome single nucleotide polymorphism (S ...[more]

PMID: 30643196

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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

POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33.

Publications

POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33.

Similar Datasets

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