A genome-wide association study identified PTPN2 as a population-specific susceptibility gene locus for primary biliary cholangitis.
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Hitomi Yuki, Ueno Kazuko, Aiba Yoshihiro, Nishida Nao, Kono Michihiro, Sugihara Mitsuki, Kawai Yosuke, Kawashima Minae, Khor Seik-Soon, Sugi Kazuhiro, Kouno Hirotaka, Kohno Hiroshi, Naganuma Atsushi, Iwamoto Satoru, Katsushima Shinji, Furuta Kiyoshi, Nikami Toshiki, Mannami Tomohiko, Yamashita Tsutomu, Ario Keisuke, Komatsu Tatsuji, Makita Fujio, Shimada Masaaki, Hirashima Noboru, Yokohama Shiro, Nishimura Hideo, Sugimoto Rie, Komura Takuya, Ota Hajime, Kojima Motoyuki, Nakamuta Makoto, Fujimori Naoyuki, Yoshizawa Kaname, Mano Yutaka, Takahashi Hironao, Hirooka Kana, Tsuruta Satoru, Sato Takeaki, Yamasaki Kazumi, Kugiyama Yuki, Motoyoshi Yasuhide, Suehiro Tomoyuki, Saeki Akira, Matsumoto Kosuke, Nagaoka Shinya, Abiru Seigo, Yatsuhashi Hiroshi, Ito Masahiro, Kawata Kazuhito, Takaki Akinobu, Arai Kuniaki, Arinaga-Hino Teruko, Abe Masanori, Harada Masaru, Taniai Makiko, Zeniya Mikio, Ohira Hiromasa, Shimoda Shinji, Komori Atsumasa, Tanaka Atsushi, Ishigaki Kazuyoshi, Nagasaki Masao, Tokunaga Katsushi, Nakamura Minoru
Аннотация
APPROACH AND RESULTS: Protein tyrosine phosphatase nonreceptor type 2 ( PTPN2) was identified as a novel PBC susceptibility gene locus through GWAS and subsequent genome-wide meta-analysis involving 2181 cases and 2699 controls from the Japanese population (GWAS-lead variant: rs8098858, p = 2.6 × 10 -8 ). In silico and in vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells and plasmacytoid dendritic cells. Infiltration of PTPN2-positive T-cells and plasmacytoid dendritic cells was confirmed in the portal area of the PBC liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758.
CONCLUSIONS: PTPN2 , a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC through an insufficient negative feedback loop caused by the risk allele of rs2292758 in IFN-γ signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment.