タニアイ　マキコ   TANIAI Makiko   谷合　麻紀子    所属   医学部 医学科（東京女子医科大学病院）    職種   准教授
論文種別	原著
言語種別	英語
査読の有無	査読なし
表題	A genome-wide association study identified PTPN2 as a population-specific susceptibility gene locus for primary biliary cholangitis
掲載誌名	正式名：Hepatology 略　 称：Hepatology ISSNコード：15273350/02709139
掲載区分	国外
巻・号・頁	80(4),pp.776-790
著者・共著者	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, NAGAMURA 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, AIBU 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, et.al
発行年月	2024/10
概要	BACKGROUND AND AIMS:Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-nonspecific) and nonshared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC.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.
DOI	10.1097/HEP.0000000000000894
PMID	38652555