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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number102
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

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Glucosyltransferases
Cholangitis
Single Nucleotide Polymorphism
Genome-Wide Association Study
Chromosomes
Genes
Proteins
Genome
Population
Intrahepatic Bile Ducts
Computer Simulation
Autoimmune Diseases
Meta-Analysis
Liver Diseases

All Science Journal Classification (ASJC) codes

  • General

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POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33. / Hitomi, Yuki; Ueno, Kazuko; Kawai, Yosuke; Nishida, Nao; Kojima, Kaname; Kawashima, Minae; Aiba, Yoshihiro; Nakamura, Hitomi; Kouno, Hiroshi; Kouno, Hirotaka; Ohta, Hajime; Sugi, Kazuhiro; Nikami, Toshiki; Yamashita, Tsutomu; Katsushima, Shinji; Komeda, Toshiki; Ario, Keisuke; Naganuma, Atsushi; Shimada, Masaaki; Hirashima, Noboru; Yoshizawa, Kaname; Makita, Fujio; Furuta, Kiyoshi; Kikuchi, Masahiro; Naeshiro, Noriaki; Takahashi, Hironao; Mano, Yutaka; Yamashita, Haruhiro; Matsushita, Kouki; Tsunematsu, Seiji; Yabuuchi, Iwao; Nishimura, Hideo; Shimada, Yusuke; Yamauchi, Kazuhiko; Komatsu, Tatsuji; Sugimoto, Rie; Sakai, Hironori; Mita, Eiji; Koda, Masaharu; Nakamura, Yoko; Kamitsukasa, Hiroshi; Sato, Takeaki; Nakamuta, Makoto; Masaki, Naohiko; Takikawa, Hajime; Tanaka, Atsushi; Ohira, Hiromasa; Zeniya, Mikio; Abe, Masanori; Kaneko, Shuichi; Honda, Masao; Arai, Kuniaki; Arinaga-Hino, Teruko; Hashimoto, Etsuko; Taniai, Makiko; Umemura, Takeji; Joshita, Satoru; Nakao, Kazuhiko; Ichikawa, Tatsuki; Shibata, Hidetaka; Takaki, Akinobu; Yamagiwa, Satoshi; Seike, Masataka; Sakisaka, Shotaro; Takeyama, Yasuaki; Harada, Masaru; Senju, Michio; Yokosuka, Osamu; Kanda, Tatsuo; Ueno, Yoshiyuki; Ebinuma, Hirotoshi; Himoto, Takashi; Murata, Kazumoto; Shimoda, Shinji; Nagaoka, Shinya; Abiru, Seigo; Komori, Atsumasa; Migita, Kiyoshi; Ito, Masahiro; Yatsuhashi, Hiroshi; Maehara, Yoshihiko; Uemoto, Shinji; Kokudo, Norihiro; Nagasaki, Masao; Tokunaga, Katsushi; Nakamura, Minoru.

In: Scientific reports, Vol. 9, No. 1, 102, 01.12.2019.

Research output: Contribution to journalArticle

Hitomi, Y, Ueno, K, Kawai, Y, Nishida, N, Kojima, K, Kawashima, M, Aiba, Y, Nakamura, H, Kouno, H, Kouno, H, Ohta, H, Sugi, K, Nikami, T, Yamashita, T, Katsushima, S, Komeda, T, Ario, K, Naganuma, A, Shimada, M, Hirashima, N, Yoshizawa, K, Makita, F, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Yamashita, H, Matsushita, K, Tsunematsu, S, Yabuuchi, I, Nishimura, H, Shimada, Y, Yamauchi, K, Komatsu, T, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Nakamura, Y, Kamitsukasa, H, Sato, T, Nakamuta, M, Masaki, N, Takikawa, H, Tanaka, A, Ohira, H, Zeniya, M, Abe, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Takaki, A, Yamagiwa, S, Seike, M, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Ebinuma, H, Himoto, T, Murata, K, Shimoda, S, Nagaoka, S, Abiru, S, Komori, A, Migita, K, Ito, M, Yatsuhashi, H, Maehara, Y, Uemoto, S, Kokudo, N, Nagasaki, M, Tokunaga, K & Nakamura, M 2019, 'POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33', Scientific reports, vol. 9, no. 1, 102. https://doi.org/10.1038/s41598-018-36490-1
Hitomi, Yuki ; Ueno, Kazuko ; Kawai, Yosuke ; Nishida, Nao ; Kojima, Kaname ; Kawashima, Minae ; Aiba, Yoshihiro ; Nakamura, Hitomi ; Kouno, Hiroshi ; Kouno, Hirotaka ; Ohta, Hajime ; Sugi, Kazuhiro ; Nikami, Toshiki ; Yamashita, Tsutomu ; Katsushima, Shinji ; Komeda, Toshiki ; Ario, Keisuke ; Naganuma, Atsushi ; Shimada, Masaaki ; Hirashima, Noboru ; Yoshizawa, Kaname ; Makita, Fujio ; Furuta, Kiyoshi ; Kikuchi, Masahiro ; Naeshiro, Noriaki ; Takahashi, Hironao ; Mano, Yutaka ; Yamashita, Haruhiro ; Matsushita, Kouki ; Tsunematsu, Seiji ; Yabuuchi, Iwao ; Nishimura, Hideo ; Shimada, Yusuke ; Yamauchi, Kazuhiko ; Komatsu, Tatsuji ; Sugimoto, Rie ; Sakai, Hironori ; Mita, Eiji ; Koda, Masaharu ; Nakamura, Yoko ; Kamitsukasa, Hiroshi ; Sato, Takeaki ; Nakamuta, Makoto ; Masaki, Naohiko ; Takikawa, Hajime ; Tanaka, Atsushi ; Ohira, Hiromasa ; Zeniya, Mikio ; Abe, Masanori ; Kaneko, Shuichi ; Honda, Masao ; Arai, Kuniaki ; Arinaga-Hino, Teruko ; Hashimoto, Etsuko ; Taniai, Makiko ; Umemura, Takeji ; Joshita, Satoru ; Nakao, Kazuhiko ; Ichikawa, Tatsuki ; Shibata, Hidetaka ; Takaki, Akinobu ; Yamagiwa, Satoshi ; Seike, Masataka ; Sakisaka, Shotaro ; Takeyama, Yasuaki ; Harada, Masaru ; Senju, Michio ; Yokosuka, Osamu ; Kanda, Tatsuo ; Ueno, Yoshiyuki ; Ebinuma, Hirotoshi ; Himoto, Takashi ; Murata, Kazumoto ; Shimoda, Shinji ; Nagaoka, Shinya ; Abiru, Seigo ; Komori, Atsumasa ; Migita, Kiyoshi ; Ito, Masahiro ; Yatsuhashi, Hiroshi ; Maehara, Yoshihiko ; Uemoto, Shinji ; Kokudo, Norihiro ; Nagasaki, Masao ; Tokunaga, Katsushi ; Nakamura, Minoru. / POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33. In: Scientific reports. 2019 ; Vol. 9, No. 1.
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title = "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.",
author = "Yuki Hitomi and Kazuko Ueno and Yosuke Kawai and Nao Nishida and Kaname Kojima and Minae Kawashima and Yoshihiro Aiba and Hitomi Nakamura and Hiroshi Kouno and Hirotaka Kouno and Hajime Ohta and Kazuhiro Sugi and Toshiki Nikami and Tsutomu Yamashita and Shinji Katsushima and Toshiki Komeda and Keisuke Ario and Atsushi Naganuma and Masaaki Shimada and Noboru Hirashima and Kaname Yoshizawa and Fujio Makita and Kiyoshi Furuta and Masahiro Kikuchi and Noriaki Naeshiro and Hironao Takahashi and Yutaka Mano and Haruhiro Yamashita and Kouki Matsushita and Seiji Tsunematsu and Iwao Yabuuchi and Hideo Nishimura and Yusuke Shimada and Kazuhiko Yamauchi and Tatsuji Komatsu and Rie Sugimoto and Hironori Sakai and Eiji Mita and Masaharu Koda and Yoko Nakamura and Hiroshi Kamitsukasa and Takeaki Sato and Makoto Nakamuta and Naohiko Masaki and Hajime Takikawa and Atsushi Tanaka and Hiromasa Ohira and Mikio Zeniya and Masanori Abe and Shuichi Kaneko and Masao Honda and Kuniaki Arai and Teruko Arinaga-Hino and Etsuko Hashimoto and Makiko Taniai and Takeji Umemura and Satoru Joshita and Kazuhiko Nakao and Tatsuki Ichikawa and Hidetaka Shibata and Akinobu Takaki and Satoshi Yamagiwa and Masataka Seike and Shotaro Sakisaka and Yasuaki Takeyama and Masaru Harada and Michio Senju and Osamu Yokosuka and Tatsuo Kanda and Yoshiyuki Ueno and Hirotoshi Ebinuma and Takashi Himoto and Kazumoto Murata and Shinji Shimoda and Shinya Nagaoka and Seigo Abiru and Atsumasa Komori and Kiyoshi Migita and Masahiro Ito and Hiroshi Yatsuhashi and Yoshihiko Maehara and Shinji Uemoto and Norihiro Kokudo and Masao Nagasaki and Katsushi Tokunaga and Minoru Nakamura",
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T1 - POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33

AU - Hitomi, Yuki

AU - Ueno, Kazuko

AU - Kawai, Yosuke

AU - Nishida, Nao

AU - Kojima, Kaname

AU - Kawashima, Minae

AU - Aiba, Yoshihiro

AU - Nakamura, Hitomi

AU - Kouno, Hiroshi

AU - Kouno, Hirotaka

AU - Ohta, Hajime

AU - Sugi, Kazuhiro

AU - Nikami, Toshiki

AU - Yamashita, Tsutomu

AU - Katsushima, Shinji

AU - Komeda, Toshiki

AU - Ario, Keisuke

AU - Naganuma, Atsushi

AU - Shimada, Masaaki

AU - Hirashima, Noboru

AU - Yoshizawa, Kaname

AU - Makita, Fujio

AU - Furuta, Kiyoshi

AU - Kikuchi, Masahiro

AU - Naeshiro, Noriaki

AU - Takahashi, Hironao

AU - Mano, Yutaka

AU - Yamashita, Haruhiro

AU - Matsushita, Kouki

AU - Tsunematsu, Seiji

AU - Yabuuchi, Iwao

AU - Nishimura, Hideo

AU - Shimada, Yusuke

AU - Yamauchi, Kazuhiko

AU - Komatsu, Tatsuji

AU - Sugimoto, Rie

AU - Sakai, Hironori

AU - Mita, Eiji

AU - Koda, Masaharu

AU - Nakamura, Yoko

AU - Kamitsukasa, Hiroshi

AU - Sato, Takeaki

AU - Nakamuta, Makoto

AU - Masaki, Naohiko

AU - Takikawa, Hajime

AU - Tanaka, Atsushi

AU - Ohira, Hiromasa

AU - Zeniya, Mikio

AU - Abe, Masanori

AU - Kaneko, Shuichi

AU - Honda, Masao

AU - Arai, Kuniaki

AU - Arinaga-Hino, Teruko

AU - Hashimoto, Etsuko

AU - Taniai, Makiko

AU - Umemura, Takeji

AU - Joshita, Satoru

AU - Nakao, Kazuhiko

AU - Ichikawa, Tatsuki

AU - Shibata, Hidetaka

AU - Takaki, Akinobu

AU - Yamagiwa, Satoshi

AU - Seike, Masataka

AU - Sakisaka, Shotaro

AU - Takeyama, Yasuaki

AU - Harada, Masaru

AU - Senju, Michio

AU - Yokosuka, Osamu

AU - Kanda, Tatsuo

AU - Ueno, Yoshiyuki

AU - Ebinuma, Hirotoshi

AU - Himoto, Takashi

AU - Murata, Kazumoto

AU - Shimoda, Shinji

AU - Nagaoka, Shinya

AU - Abiru, Seigo

AU - Komori, Atsumasa

AU - Migita, Kiyoshi

AU - Ito, Masahiro

AU - Yatsuhashi, Hiroshi

AU - Maehara, Yoshihiko

AU - Uemoto, Shinji

AU - Kokudo, Norihiro

AU - Nagasaki, Masao

AU - Tokunaga, Katsushi

AU - Nakamura, Minoru

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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