Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population

Minoru Nakamura, Nao Nishida, Minae Kawashima, Yoshihiro Aiba, Atsushi Tanaka, Michio Yasunami, Hitomi Nakamura, Atsumasai Komori, Makoto Nakamuta, Mikio Zeniya, Etsuko Hashimoto, Hiromasa Ohira, Kazuhide Yamamoto, Morikazu Onji, Shuichi Kaneko, Masao Honda, Satoshi Yamagiwa, Kazuhiko Nakao, Takafumi Ichida, Hajime Takikawa & 60 others Masataka Seike, Takeji Umemura, Yoshiyuki Ueno, Shotaro Sakisaka, Kentaro Kikuchi, Hirotoshi Ebinuma, Noriyo Yamashiki, Sumito Tamura, Yasuhiko Sugawara, Akira Mori, Shintaro Yagi, Ken Shirabe, Akinobu Taketomi, Kuniaki Arai, Kyoko Monoe, Tatsuki Ichikawa, Makiko Taniai, Yasuhiro Miyake, Teru Kumagi, Masanori Abe, Kaname Yoshizawa, Satoru Joshita, Shinji Shimoda, Koichi Honda, Hiroki Takahashi, Katsuji Hirano, Yasuaki Takeyama, Kenichi Harada, Kiyoshi Migita, Masahiro Ito, Hiroshi Yatsuhashi, Nobuyoshi Fukushima, Hajime Ota, Tatsuji Komatsu, Takeo Saoshiro, Jinya Ishida, Hirotsugu Kouno, Hirotaka Kouno, Michiyasu Yagura, Masakazu Kobayashi, Toyokichi Muro, Naohiko Masaki, Keiichi Hirata, Yukio Watanabe, Yoko Nakamura, Masaaki Shimada, Noboru Hirashima, Toshiki Komeda, Kazuhiro Sugi, Michiaki Koga, Keisuke Ario, Eiichi Takesaki, Yoshihiko Maehara, Shinji Uemoto, Norihiro Kokudo, Hirohito Tsubouchi, Masashi Mizokami, Yasuni Nakanuma, Katsushi Tokunaga, Hiromi Ishibashi

Research output: Contribution to journalArticle

141 Citations (Scopus)

Abstract

For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] = 1.56, p = 2.84 × 10-14 for rs4979462, and combined OR = 1.39, p = 2.38 × 10-8 for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined p = 3.66 × 10-8, 3.66 × 10-9, and 3.04 × 10-9, respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC (combined p = 1.11 × 10-6 and 1.42 × 10-7, respectively) in the Japanese population. These observations indicated the existence of ethnic differences in genetic susceptibility loci to PBC and the importance of TNF signaling and B cell differentiation for the development of PBC in individuals of European descent and Japanese individuals.

Original languageEnglish
Pages (from-to)721-728
Number of pages8
JournalAmerican Journal of Human Genetics
Volume91
Issue number4
DOIs
Publication statusPublished - 2012 Oct 5
Externally publishedYes

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Biliary Liver Cirrhosis
Genome-Wide Association Study
Population
HLA Antigens
Odds Ratio
Genetic Loci
Genetic Predisposition to Disease
Cell Differentiation
B-Lymphocytes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population. / Nakamura, Minoru; Nishida, Nao; Kawashima, Minae; Aiba, Yoshihiro; Tanaka, Atsushi; Yasunami, Michio; Nakamura, Hitomi; Komori, Atsumasai; Nakamuta, Makoto; Zeniya, Mikio; Hashimoto, Etsuko; Ohira, Hiromasa; Yamamoto, Kazuhide; Onji, Morikazu; Kaneko, Shuichi; Honda, Masao; Yamagiwa, Satoshi; Nakao, Kazuhiko; Ichida, Takafumi; Takikawa, Hajime; Seike, Masataka; Umemura, Takeji; Ueno, Yoshiyuki; Sakisaka, Shotaro; Kikuchi, Kentaro; Ebinuma, Hirotoshi; Yamashiki, Noriyo; Tamura, Sumito; Sugawara, Yasuhiko; Mori, Akira; Yagi, Shintaro; Shirabe, Ken; Taketomi, Akinobu; Arai, Kuniaki; Monoe, Kyoko; Ichikawa, Tatsuki; Taniai, Makiko; Miyake, Yasuhiro; Kumagi, Teru; Abe, Masanori; Yoshizawa, Kaname; Joshita, Satoru; Shimoda, Shinji; Honda, Koichi; Takahashi, Hiroki; Hirano, Katsuji; Takeyama, Yasuaki; Harada, Kenichi; Migita, Kiyoshi; Ito, Masahiro; Yatsuhashi, Hiroshi; Fukushima, Nobuyoshi; Ota, Hajime; Komatsu, Tatsuji; Saoshiro, Takeo; Ishida, Jinya; Kouno, Hirotsugu; Kouno, Hirotaka; Yagura, Michiyasu; Kobayashi, Masakazu; Muro, Toyokichi; Masaki, Naohiko; Hirata, Keiichi; Watanabe, Yukio; Nakamura, Yoko; Shimada, Masaaki; Hirashima, Noboru; Komeda, Toshiki; Sugi, Kazuhiro; Koga, Michiaki; Ario, Keisuke; Takesaki, Eiichi; Maehara, Yoshihiko; Uemoto, Shinji; Kokudo, Norihiro; Tsubouchi, Hirohito; Mizokami, Masashi; Nakanuma, Yasuni; Tokunaga, Katsushi; Ishibashi, Hiromi.

In: American Journal of Human Genetics, Vol. 91, No. 4, 05.10.2012, p. 721-728.

Research output: Contribution to journalArticle

Nakamura, M, Nishida, N, Kawashima, M, Aiba, Y, Tanaka, A, Yasunami, M, Nakamura, H, Komori, A, Nakamuta, M, Zeniya, M, Hashimoto, E, Ohira, H, Yamamoto, K, Onji, M, Kaneko, S, Honda, M, Yamagiwa, S, Nakao, K, Ichida, T, Takikawa, H, Seike, M, Umemura, T, Ueno, Y, Sakisaka, S, Kikuchi, K, Ebinuma, H, Yamashiki, N, Tamura, S, Sugawara, Y, Mori, A, Yagi, S, Shirabe, K, Taketomi, A, Arai, K, Monoe, K, Ichikawa, T, Taniai, M, Miyake, Y, Kumagi, T, Abe, M, Yoshizawa, K, Joshita, S, Shimoda, S, Honda, K, Takahashi, H, Hirano, K, Takeyama, Y, Harada, K, Migita, K, Ito, M, Yatsuhashi, H, Fukushima, N, Ota, H, Komatsu, T, Saoshiro, T, Ishida, J, Kouno, H, Kouno, H, Yagura, M, Kobayashi, M, Muro, T, Masaki, N, Hirata, K, Watanabe, Y, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Sugi, K, Koga, M, Ario, K, Takesaki, E, Maehara, Y, Uemoto, S, Kokudo, N, Tsubouchi, H, Mizokami, M, Nakanuma, Y, Tokunaga, K & Ishibashi, H 2012, 'Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population', American Journal of Human Genetics, vol. 91, no. 4, pp. 721-728. https://doi.org/10.1016/j.ajhg.2012.08.010
Nakamura, Minoru ; Nishida, Nao ; Kawashima, Minae ; Aiba, Yoshihiro ; Tanaka, Atsushi ; Yasunami, Michio ; Nakamura, Hitomi ; Komori, Atsumasai ; Nakamuta, Makoto ; Zeniya, Mikio ; Hashimoto, Etsuko ; Ohira, Hiromasa ; Yamamoto, Kazuhide ; Onji, Morikazu ; Kaneko, Shuichi ; Honda, Masao ; Yamagiwa, Satoshi ; Nakao, Kazuhiko ; Ichida, Takafumi ; Takikawa, Hajime ; Seike, Masataka ; Umemura, Takeji ; Ueno, Yoshiyuki ; Sakisaka, Shotaro ; Kikuchi, Kentaro ; Ebinuma, Hirotoshi ; Yamashiki, Noriyo ; Tamura, Sumito ; Sugawara, Yasuhiko ; Mori, Akira ; Yagi, Shintaro ; Shirabe, Ken ; Taketomi, Akinobu ; Arai, Kuniaki ; Monoe, Kyoko ; Ichikawa, Tatsuki ; Taniai, Makiko ; Miyake, Yasuhiro ; Kumagi, Teru ; Abe, Masanori ; Yoshizawa, Kaname ; Joshita, Satoru ; Shimoda, Shinji ; Honda, Koichi ; Takahashi, Hiroki ; Hirano, Katsuji ; Takeyama, Yasuaki ; Harada, Kenichi ; Migita, Kiyoshi ; Ito, Masahiro ; Yatsuhashi, Hiroshi ; Fukushima, Nobuyoshi ; Ota, Hajime ; Komatsu, Tatsuji ; Saoshiro, Takeo ; Ishida, Jinya ; Kouno, Hirotsugu ; Kouno, Hirotaka ; Yagura, Michiyasu ; Kobayashi, Masakazu ; Muro, Toyokichi ; Masaki, Naohiko ; Hirata, Keiichi ; Watanabe, Yukio ; Nakamura, Yoko ; Shimada, Masaaki ; Hirashima, Noboru ; Komeda, Toshiki ; Sugi, Kazuhiro ; Koga, Michiaki ; Ario, Keisuke ; Takesaki, Eiichi ; Maehara, Yoshihiko ; Uemoto, Shinji ; Kokudo, Norihiro ; Tsubouchi, Hirohito ; Mizokami, Masashi ; Nakanuma, Yasuni ; Tokunaga, Katsushi ; Ishibashi, Hiromi. / Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population. In: American Journal of Human Genetics. 2012 ; Vol. 91, No. 4. pp. 721-728.
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abstract = "For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] = 1.56, p = 2.84 × 10-14 for rs4979462, and combined OR = 1.39, p = 2.38 × 10-8 for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined p = 3.66 × 10-8, 3.66 × 10-9, and 3.04 × 10-9, respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC (combined p = 1.11 × 10-6 and 1.42 × 10-7, respectively) in the Japanese population. These observations indicated the existence of ethnic differences in genetic susceptibility loci to PBC and the importance of TNF signaling and B cell differentiation for the development of PBC in individuals of European descent and Japanese individuals.",
author = "Minoru Nakamura and Nao Nishida and Minae Kawashima and Yoshihiro Aiba and Atsushi Tanaka and Michio Yasunami and Hitomi Nakamura and Atsumasai Komori and Makoto Nakamuta and Mikio Zeniya and Etsuko Hashimoto and Hiromasa Ohira and Kazuhide Yamamoto and Morikazu Onji and Shuichi Kaneko and Masao Honda and Satoshi Yamagiwa and Kazuhiko Nakao and Takafumi Ichida and Hajime Takikawa and Masataka Seike and Takeji Umemura and Yoshiyuki Ueno and Shotaro Sakisaka and Kentaro Kikuchi and Hirotoshi Ebinuma and Noriyo Yamashiki and Sumito Tamura and Yasuhiko Sugawara and Akira Mori and Shintaro Yagi and Ken Shirabe and Akinobu Taketomi and Kuniaki Arai and Kyoko Monoe and Tatsuki Ichikawa and Makiko Taniai and Yasuhiro Miyake and Teru Kumagi and Masanori Abe and Kaname Yoshizawa and Satoru Joshita and Shinji Shimoda and Koichi Honda and Hiroki Takahashi and Katsuji Hirano and Yasuaki Takeyama and Kenichi Harada and Kiyoshi Migita and Masahiro Ito and Hiroshi Yatsuhashi and Nobuyoshi Fukushima and Hajime Ota and Tatsuji Komatsu and Takeo Saoshiro and Jinya Ishida and Hirotsugu Kouno and Hirotaka Kouno and Michiyasu Yagura and Masakazu Kobayashi and Toyokichi Muro and Naohiko Masaki and Keiichi Hirata and Yukio Watanabe and Yoko Nakamura and Masaaki Shimada and Noboru Hirashima and Toshiki Komeda and Kazuhiro Sugi and Michiaki Koga and Keisuke Ario and Eiichi Takesaki and Yoshihiko Maehara and Shinji Uemoto and Norihiro Kokudo and Hirohito Tsubouchi and Masashi Mizokami and Yasuni Nakanuma and Katsushi Tokunaga and Hiromi Ishibashi",
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TY - JOUR

T1 - Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population

AU - Nakamura, Minoru

AU - Nishida, Nao

AU - Kawashima, Minae

AU - Aiba, Yoshihiro

AU - Tanaka, Atsushi

AU - Yasunami, Michio

AU - Nakamura, Hitomi

AU - Komori, Atsumasai

AU - Nakamuta, Makoto

AU - Zeniya, Mikio

AU - Hashimoto, Etsuko

AU - Ohira, Hiromasa

AU - Yamamoto, Kazuhide

AU - Onji, Morikazu

AU - Kaneko, Shuichi

AU - Honda, Masao

AU - Yamagiwa, Satoshi

AU - Nakao, Kazuhiko

AU - Ichida, Takafumi

AU - Takikawa, Hajime

AU - Seike, Masataka

AU - Umemura, Takeji

AU - Ueno, Yoshiyuki

AU - Sakisaka, Shotaro

AU - Kikuchi, Kentaro

AU - Ebinuma, Hirotoshi

AU - Yamashiki, Noriyo

AU - Tamura, Sumito

AU - Sugawara, Yasuhiko

AU - Mori, Akira

AU - Yagi, Shintaro

AU - Shirabe, Ken

AU - Taketomi, Akinobu

AU - Arai, Kuniaki

AU - Monoe, Kyoko

AU - Ichikawa, Tatsuki

AU - Taniai, Makiko

AU - Miyake, Yasuhiro

AU - Kumagi, Teru

AU - Abe, Masanori

AU - Yoshizawa, Kaname

AU - Joshita, Satoru

AU - Shimoda, Shinji

AU - Honda, Koichi

AU - Takahashi, Hiroki

AU - Hirano, Katsuji

AU - Takeyama, Yasuaki

AU - Harada, Kenichi

AU - Migita, Kiyoshi

AU - Ito, Masahiro

AU - Yatsuhashi, Hiroshi

AU - Fukushima, Nobuyoshi

AU - Ota, Hajime

AU - Komatsu, Tatsuji

AU - Saoshiro, Takeo

AU - Ishida, Jinya

AU - Kouno, Hirotsugu

AU - Kouno, Hirotaka

AU - Yagura, Michiyasu

AU - Kobayashi, Masakazu

AU - Muro, Toyokichi

AU - Masaki, Naohiko

AU - Hirata, Keiichi

AU - Watanabe, Yukio

AU - Nakamura, Yoko

AU - Shimada, Masaaki

AU - Hirashima, Noboru

AU - Komeda, Toshiki

AU - Sugi, Kazuhiro

AU - Koga, Michiaki

AU - Ario, Keisuke

AU - Takesaki, Eiichi

AU - Maehara, Yoshihiko

AU - Uemoto, Shinji

AU - Kokudo, Norihiro

AU - Tsubouchi, Hirohito

AU - Mizokami, Masashi

AU - Nakanuma, Yasuni

AU - Tokunaga, Katsushi

AU - Ishibashi, Hiromi

PY - 2012/10/5

Y1 - 2012/10/5

N2 - For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] = 1.56, p = 2.84 × 10-14 for rs4979462, and combined OR = 1.39, p = 2.38 × 10-8 for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined p = 3.66 × 10-8, 3.66 × 10-9, and 3.04 × 10-9, respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC (combined p = 1.11 × 10-6 and 1.42 × 10-7, respectively) in the Japanese population. These observations indicated the existence of ethnic differences in genetic susceptibility loci to PBC and the importance of TNF signaling and B cell differentiation for the development of PBC in individuals of European descent and Japanese individuals.

AB - For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] = 1.56, p = 2.84 × 10-14 for rs4979462, and combined OR = 1.39, p = 2.38 × 10-8 for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined p = 3.66 × 10-8, 3.66 × 10-9, and 3.04 × 10-9, respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC (combined p = 1.11 × 10-6 and 1.42 × 10-7, respectively) in the Japanese population. These observations indicated the existence of ethnic differences in genetic susceptibility loci to PBC and the importance of TNF signaling and B cell differentiation for the development of PBC in individuals of European descent and Japanese individuals.

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