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原発性胆汁性胆管炎(PBC)研究
Research for Primary biliary cholangitis (PBC)

We explore the development mechanism of PBC by searching for susceptibility gene of exhaustive PBC over the whole genome.

研究背景

原発性胆汁性胆管炎(PBC)は、肝臓内にある小さな胆管(胆汁排泄のための管)に炎症が起こり、胆管が破壊され胆汁が肝臓にうっ滞することによって起こる病気です。その発症には、自己の免疫システムが誤って自己の組織(胆管細胞)を攻撃してしまう「自己免疫」の関与が示唆されていますが、その発症や病態に関しては、多くが不明なままとなっています。

研究アプローチ

私たちは、長崎大学の中村稔教授、京都大学学際融合教育研究推進センターの長崎正朗特定教授、などとの共同研究により、ゲノムワイド関連解析(GWAS)という手法を用いて、全ゲノムに渡る網羅的なPBCの感受性遺伝子探索を実施しています。

  • 1. 東北大学東北メディカル・メガバンク機構が保有する2,049人の日本人全ゲノムシークエンス情報(2KJPN)をリファレンスとした、全ゲノムインピュテーション解析
  • 2. 欧米のPBC-consortiumとの共同研究によるtrans-ethnic meta-analysis
  • 3. PBCの重症度や病型、自己抗体産生を規定する遺伝子の探索
  • 4. 疾患感受性遺伝子領域内に存在し、発症に直接関与する第一義的な遺伝子多型の同定
  • 5. 肝組織におけるマイクロアレイ遺伝子発現データとGWASとのマルチオミックス解析
  • 6. Regional Heritability Mapping法を用いた新規疾患感受性遺伝子の同定
  • 7. PBCを対象としたHLA解析

主な成果

全ゲノムに渡るおよそ60万ヶ所のマーカーSNPに対し、PBC患者1,274例・健常者1,091例を用いたGWASを実施した結果、HLA遺伝子群、TNFSF15、POU2AF1が疾患感受性との強い関連を示しました。(Nakamura M et al, Am J Hum Genet 2012)

サンプル数を拡大したGWAS (PBC患者1,406例・健常者7,541例)にて、合計8ヶ所の疾患感受性遺伝子を同定しました。(Kawashima M et al, Hum Mol Genet 2017)

さらに、新たに収集したサンプルを対象に実施したGWAS(PBC患者668例・健常者480例)と、これまでのGWASとのメタ・アナリシスにて、これまでにはアジア人で報告されていなかった新規疾患感受性遺伝子領域Chromosome 3q13.33を同定しました。(Hitomi Y, Ueno K, et al, Sci Rep 2019)

本研究に関する文献

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. POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33. Sci Rep 9: 102, 2019.
Hitomi Y, Nakatani K, Kojima K, Nishida N, Kawai Y, Kawashima M, Aiba Y, Nagasaki M, Nakamura M, Tokunaga K. NFKB1 and MANBA confer disease susceptibility to primary biliary cholangitis via independent putative primary functional variants. Cell Mol Gastroenterol Hepatol 7: 515-532, 2019.
Aiba Y, Harada K, Ito M, Suematsu T, Aishima S, Hitomi Y, Nishida N, Kawashima M, Takatsuki M, Eguchi S, Shimoda S, Nakamura H, Komori A, Abiru S, Nagaoka S, Migita K, Yatsuhashi H, Tokunaga K, Nakamura M. Increased expression and altered localization of cathepsin Z are associated with progression to jaundice stage in primary biliary cholangitis. Sci Rep 8: 11808, 2018.
Nishida N, Aiba Y, Hitomi Y, Kawashima M, Kojima K, Kawai Y, Ueno K, Nakamura H, Yamashiki N, Tanaka T, Tamura S, Mori A, Yagi S, Soejima Y, Yoshizumi T, Takatsuki M, Tanaka A, Harada K, Shimoda S, Komori A, Eguchi S, Maehara Y, Uemoto S, Kokudo N, Nagasaki M, Tokunaga K, Nakamura M. NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese population. Sci Rep 8: 8071, 2018.
Im C, Sapkota Y, Moon W, Kawashima M, Nakamura M, Tokunaga K, Yasui Y. Genome-wide haplotype association analysis of primary biliary cholangitis risk in Japanese. Sci Rep 8: 7806, 2018.
Yasunami M, Nakamura H , Tokunaga K, Kawashima M, Nishida N, Hitomi Y, Nakamura M. Principal contribution of HLA-DQ alleles, DQB1*06:04 and DQB1*03:01, to disease resistance against primary biliary cholangitis in a Japanese population. Sci Rep 7:11093, 2017.
Hitomi Y (#), Kojima K (#), Kawashima M, Kawai Y, Nishida N, Aiba Y, Yasunami M, Nagasaki M, Nakamura M, Tokunaga K. Identification of the functional variant driving ORMDL3 and GSDMB expression in human chromosome 17q12-21 in primary biliary cholangitis. (#Equally contributed) Sci Rep 7: 2904, 2017.
Kawashima M (#), Hitomi Y (#), Aiba Y (#), Nishida N (#), Kojima K (#), Kawai Y, Nakamura H, Tanaka A, Zeniya M, Hashimoto E, Ohira H, Yamamoto K, Abe M, Nakao K, Yamagiwa S, Kaneko S, Honda M, Umemura T, Ichida T, Seike M, Sakisaka S, Harada M, Yokosuka O, Ueno Y, Senju M, Kanda T, Shibata H, Himoto T, Murata K, Miyake Y, Ebinuma H, Taniai M, Joshita S, Nikami T, Ota H, Kouno H, Kouno H, Nakamura M, Kohjima M, Komatsu T, Komeda T, Ohara Y, Muro T, Yamashita T, Yoshizawa K, Kamitsukasa Y, Nakamura Y, Shimada M, Hirashima N, Sugi K, Ario K, Takesaki E, Naganuma A, Mano H, Yamashita H, Matsushita K, Yamauchi K, Makita F, Nishimura H, Furuta K, Takahashi N, Masaki N, Tanaka T, Tamura S, Mori A, Yagi S, Shirabe K, Komori A, Migita K, Ito M, Nagaoka S, Abiru S, Yatsuhashi H, Yasunami M, Shimoda S, Harada K, Egawa H, Maehara Y, Uemoto S, Kokubo N, Takikawa H, Ishibashi H, Chayama K, Mizokami M, Nagasaki M, Tokunaga K, Nakamura M. Genome-wide association studies identify PRKCB as a genetic susceptibility locus for primary biliary cirrhosis in the Japanese population. (#Equally contributed) Hum Mol Genet 26(3):650-659, 2017
Sun YH, Irwanto A, Toyo-oka L, Hong MH, Liu H, Andiappan AK, Choi HC, Hitomi Y, Yu GQ, Yu YX, Bao FF, Wang C, Fu X, Yue ZH, Wang HL, Zhang HM, Kawashima M, Kojima K, Nagasaki M, Nakamura M, Yang SK, Ye BD, Denise Y, Rotzschke O, Song KY, Tokunaga K, Zhang FR, Liu JJ. Fine-mapping analysis revealed complex pleiotropic effect and tissue-specific regulatory mechanism of TNFSF15 in primary biliary cholangitis, Crohn's disease and leprosy. Sci Rep 6: 31429, 2016.
Aiba Y, Yamazaki K, Nishida N, Kawashima M, Hitomi Y, Nakamura H, Komori A, Fuyuno Y, Takahashi A, Kawaguchi T, Takazoe M, Suzuki Y, Motoya S, Matsui T, Esaki M, Matsumoto T, Kubo M, Tokunaga K, Nakamura M. Disease susceptibility genes shared by primary biliary cirrhosis and Crohn's disease in the Japanese population. J Hum Genet 60(9):525-31, 2015.
Hitomi Y, Kawashima M, Aiba Y, Nishida N, Matsuhashi M, Okazaki H, Nakamura M, Tokunaga K. Human primary biliary cirrhosis-susceptible allele of rs4979462 enhances TNFSF15 expression by binding NF-1. Hum Genet 134(7):737-47, 2015.
Aiba Y, Harada K, Komori A, Ito M, Shimoda S, Nakamura H, Nagaoka S, Abiru S, Migita K, Ishibashi H, Nakanuma Y, Nishida N, Kawashima M, Tokunaga K, Yatsuhashi H, Nakamura M.Systemic and local expression levels of TNF-like ligand 1A and its decoy receptor 3 are increased in primary biliary cirrhosis. Liver Int. 34(5):679-88, 2014.
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: Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population.Am J Hum Genet, 91(4):721-8, 2012.