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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

Gervais, Olivier, Kazuko Ueno, Yosuke Kawai, Yuki Hitomi, Yoshihiro Aiba, Mayumi Ueta, Minoru Nakamura, Katsushi Tokunaga, and Masao Nagasaki. Regional Heritability Mapping Identifies Several Novel Loci (STAT4, ULK4, and KCNH5) for Primary Biliary Cholangitis in the Japanese Population. European Journal of Human Genetics. 2021.
Cordell, Heather J., James J. Fryett, Kazuko Ueno, Rebecca Darlay, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Nao Nishida, Seik-Soon Khor, Olivier Gervais, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Ruqi Tang, Yongyong Shi, Zhiqiang Li, Brian D. Juran, Elizabeth J. Atkinson, Alessio Gerussi, Marco Carbone, Rosanna Asselta, Angela Cheung, Mariza de Andrade, Aris Baras, Julie Horowitz, Manuel A. R. Ferreira, Dylan Sun, David E. Jones, Steven Flack, Ann Spicer, Victoria L. Mulcahy, Jinyoung Byan, Younghun Han, Richard N. Sandford, Konstantinos N. Lazaridis, Christopher I. Amos, Gideon M. Hirschfield, Michael F. Seldin, Pietro Invernizzi, Katherine A. Siminovitch, Xiong Ma, Minoru Nakamura, George F. Mells, Katherine A. Siminovitch, Gideon M. Hirschfield, Andrew Mason, Catherine Vincent, Gang Xie, Jinyi Zhang, Ruqi Tang, Xiong Ma, Zhiqiang Li, Yongyong Shi, Andrea Affronti, Piero L. Almasio, Domenico Alvaro, Pietro Andreone, Angelo Andriulli, Francesco Azzaroli, Pier Maria Battezzati, Antonio Benedetti, MariaConsiglia Bragazzi, Maurizia Brunetto, Savino Bruno, Vincenza Calvaruso, Vincenzo Cardinale, Giovanni Casella, Nora Cazzagon, Antonio Ciaccio, Barbara Coco, Agostino Colli, Guido Colloredo, Massimo Colombo, Silvia Colombo, Laura Cristoferi, Carmela Cursaro, Lory Saveria Crocè, Andrea Crosignani, Daphne D’Amato, Francesca Donato, Gianfranco Elia, Stefano Fagiuoli, Carlo Ferrari, Annarosa Floreani, Andrea Galli, Edoardo Giannini, Ignazio Grattagliano, Pietro Lampertico, Ana Lleo, Federica Malinverno, Clara Mancuso, Fabio Marra, Marco Marzioni, Sara Massironi, Alberto Mattalia, Luca Miele, Chiara Milani, Lorenzo Morini, Filomena Morisco, Luigi Muratori, Paolo Muratori, Grazia A. Niro, Sarah O’Donnell, Antonio Picciotto, Piero Portincasa, Cristina Rigamonti, Vincenzo Ronca, Floriano Rosina, Giancarlo Spinzi, Mario Strazzabosco, Mirko Tarocchi, Claudio Tiribelli, Pierluigi Toniutto, Luca Valenti, Maria Vinci, Massimo Zuin, Hitomi Nakamura, Seigo Abiru, Shinya Nagaoka, Atsumasa Komori, Hiroshi Yatsuhashi, Hiromi Ishibashi, Masahiro Ito, Kiyoshi Migita, Hiromasa Ohira, Shinji Katsushima, Atsushi Naganuma, Kazuhiro Sugi, Tatsuji Komatsu, Tomohiko Mannami, Kouki Matsushita, Kaname Yoshizawa, Fujio Makita, Toshiki Nikami, Hideo Nishimura, Hiroshi Kouno, Hirotaka Kouno, Hajime Ota, Takuya Komura, Yoko Nakamura, Masaaki Shimada, Noboru Hirashima, Toshiki Komeda, Keisuke Ario, Makoto Nakamuta, Tsutomu Yamashita, Kiyoshi Furuta, Masahiro Kikuchi, Noriaki Naeshiro, Hironao Takahashi, Yutaka Mano, Seiji Tsunematsu, Iwao Yabuuchi, Yusuke Shimada, Kazuhiko Yamauchi, Rie Sugimoto, Hironori Sakai, Eiji Mita, Masaharu Koda, Satoru Tsuruta, Hiroshi Kamitsukasa, Takeaki Sato, Naohiko Masaki, Tatsuro Kobata, Nobuyoshi Fukushima, Yukio Ohara, Toyokichi Muro, Eiichi Takesaki, Hitoshi Takaki, Tetsuo Yamamoto, Michio Kato, Yuko Nagaoki, Shigeki Hayashi, Jinya Ishida, Yukio Watanabe, Masakazu Kobayashi, Michiaki Koga, Takeo Saoshiro, Michiyasu Yagura, Keisuke Hirata, Atsushu Tanaka, Hajime Takikawa, Mikio Zeniya, Masanori Abe, Morikazu Onji, Shuichi Kaneko, Masao Honda, Kuniaki Arai, Teruko Arinaga-Hino, Etsuko Hashimoto, Makiko Taniai, Takeji Umemura, Satoru Joshita, Kazuhiko Nakao, Tatsuki Ichikawa, Hidetaka Shibata, Satoshi Yamagiwa, Masataka Seike, Koichi Honda, Shotaro Sakisaka, Yasuaki Takeyama, Masaru Harada, Michio Senju, Osamu Yokosuka, Tatsuo Kanda, Yoshiyuki Ueno, Kentaro Kikuchi, Hirotoshi Ebinuma, Takashi Himoto, Michio Yasunami, Kazumoto Murata, Masashi Mizokami, Kazuhito Kawata, Shinji Shimoda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto, Katsuji Hirano, Takafumi Ichida, Akio Ido, Hirohito Tsubouchi, Kazuaki Chayama, Kenichi Harada, Yasuni Nakanuma, Yoshihiko Maehara, Akinobu Taketomi, Ken Shirabe, Yuji Soejima, Akira Mori, Shintaro Yagi, Shinji Uemoto, H. Egawa, Tomohiro Tanaka, Noriyo Yamashiki, Sumito Tamura, Yasuhiro Sugawara, Norihiro Kokudo, Richard Sturgess, Christopher Healey, Andrew Yeoman, Anton VJ. Gunasekera, Paul Kooner, Kapil Kapur, V. Sathyanarayana, Yiannis Kallis, Javaid Subhani, Rory Harvey, Roger McCorry, Paul Rooney, David Ramanaden, Richard Evans, Thiriloganathan Mathialahan, Jaber Gasem, Christopher Shorrock, Mahesh Bhalme, Paul Southern, Jeremy A. Tibble, David A. Gorard, Susan Jones, George Mells, Victoria Mulcahy, Brijesh Srivastava, Matthew R. Foxton, Carole E. Collins, David Elphick, Mazn Karmo, Francisco Porras-Perez, Michael Mendall, Tom Yapp, Minesh Patel, Roland Ede, Joanne Sayer, James Jupp, Neil Fisher, Martyn J. Carter, Konrad Koss, Jayshri Shah, Andrzej Piotrowicz, Glyn Scott, Charles Grimley, Ian R. Gooding, Simon Williams, Judith Tidbury, Guan Lim, Kuldeep Cheent, Sass Levi, Dina Mansour, Matilda Beckley, Coral Hollywood, Terry Wong, Richard Marley, John Ramage, Harriet M. Gordon, Jo Ridpath, Theodore Ngatchu, Vijay Paul Bob Grover, Ray G. Shidrawi, George Abouda, L. Corless, Mark Narain, Ian Rees, Ashley Brown, Simon Taylor-Robinson, Joy Wilkins, Leonie Grellier, Paul Banim, Debasish Das, Michael A. Heneghan, Howard Curtis, Helen C. Matthews, Faiyaz Mohammed, Mark Aldersley, Raj Srirajaskanthan, Giles Walker, Alistair McNair, Amar Sharif, Sambit Sen, George Bird, Martin I. Prince, Geeta Prasad, Paul Kitchen, Adrian Barnardo, Chirag Oza, Nurani N. Sivaramakrishnan, Prakash Gupta, Amir Shah, Chris DJ. Evans, Subrata Saha, Katharine Pollock, Peter Bramley, Ashis Mukhopadhya, Stephen T. Barclay, Natasha McDonald, Andrew J. Bathgate, Kelvin Palmer, John F. Dillon, Simon M. Rushbrook, Robert Przemioslo, Chris McDonald, Andrew Millar, Cheh Tai, Stephen Mitchell, Jane Metcalf, Syed Shaukat, Mary Ninkovic, Udi Shmueli, Andrew Davis, Asifabbas Naqvi, Tom JW. Lee, Stephen Ryder, Jane Collier, Howard Klass, Matthew E. Cramp, Nichols Sharer, Richard Aspinall, Deb Ghosh, Andrew C. Douds, Jonathan Booth, Earl Williams, Hyder Hussaini, John Christie, Steven Mann, Douglas Thorburn, Aileen Marshall, Imran Patanwala, Aftab Ala, Julia Maltby, Ray Matthew, Chris Corbett, Sam Vyas, Saket Singhal, Dermot Gleeson, Sharat Misra, Jeff Butterworth, Keith George, Tim Harding, Andrew Douglass, Harriet Mitchison, Simon Panter, Jeremy Shearman, Gary Bray, Michael Roberts, Graham Butcher, Daniel Forton, Zahid Mahmood, Matthew Cowan, Debashis Das, Chin Lye Ch’ng, Mesbah Rahman, Gregory C. A. Whatley, Emma Wesley, Aditya Mandal, Sanjiv Jain, Stephen P. Pereira, Mark Wright, Palak Trivedi, Fiona H. Gordon, Esther Unitt, Altaf Palejwala, Andrew Austin, Vishwaraj Vemala, Allister Grant, Andrew D. Higham, Alison Brind, Ray Mathew, Mark Cox, Subramaniam Ramakrishnan, Alistair King, Simon Whalley, Jocelyn Fraser, S. J. Thomson, Andrew Bell, Voi Shim Wong, Richard Kia, Ian Gee, Richard Keld, Rupert Ransford, James Gotto, Charles Millson, Brian D. Juran, Elizabeth J. Atkinson, Angela Cheung, Mariza de Andrade, Konstantinos N. Lazaridis, Naga Chalasani, Vel Luketic, Joseph Odin, Kapil Chopra, Aris Baras, Julie Horowitz, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, John D. Overton, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Jeffrey G. Reid, Evan K. Maxwell, William Salerno, Jeffrey C. Staples, Marcus B. Jones, and Lyndon J. Mitnaul. An International Genome-Wide Meta-Analysis of Primary Biliary Cholangitis: Novel Risk Loci and Candidate Drugs. Journal of Hepatology. 2021.
Asselta R, Paraboschi EM, Gerussi A, Cordell HJ, Mells GF, Sandford RN, Jones DE, Nakamura M, Ueno K, Hitomi Y, Kawashima M, Nishida N, Tokunaga K, Nagasaki M, Tanaka A, Tang R, Li Z, Shi Y, Liu X, Xiong M, Hirschfield G, Siminovitch KA; Canadian-US PBC Consortium; Italian PBC Genetics Study Group; UK-PBC Consortium; Japan PBC-GWAS Consortium, Carbone M, Cardamone G, Duga S, Gershwin ME, Seldin MF, Invernizzi P. X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis. Gastroenterology. 2021 Jun;160(7):2483-2495.e26.
Hitomi Y, Aiba Y, Kawai Y, Kojima K, Ueno K, Nishida N, Kawashima M, Gervais O, Khor SS, Nagasaki M, Tokunaga K, Nakamura M, Tsuiji M. rs1944919 on chromosome 11q23.1 and its effector genes COLCA1/COLCA2 confer susceptibility to primary biliary cholangitis. Sci Rep. 2021 Feb 25;11(1):4557.
Ueno K, Aiba Y, Hitomi Y, Shimoda S, Nakamura H, Gervais O, Kawai Y, Kawashima M, Nishida N, Kohn SS, Kojima K, Katsushima S, Naganuma A, Sugi K, Komatsu T, Mannami T, Matsushita K, Yoshizawa K, Makita F, Nikami T, Nishimura H, Kouno H, Kouno H, Ohta H, Komura T, Tsuruta S, Yamauchi K, Kobata T, Kitasato A, Kuroki T, Abiru S, Nagaoka S, Komori A, Yatsuhashi H, Migita K, Ohira H, Tanaka A, Takikawa H, Nagasaki M, Tokunaga K, Nakamura M; PBC‐GWAS Consortium in Japan. Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis. Hepatol Commun. 2020 Mar 15;4(5):724-738.
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.