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 TakikawaMasataka 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

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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.

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    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., ... 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, 91(4), 721-728. https://doi.org/10.1016/j.ajhg.2012.08.010