Detection of susceptibility genes associated with autoimmune rheumatic diseases in the Japanese population and its translation into genome medicine.

2013 Fiscal Year Final Research Report

• Project/Area Number: 22390199
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: University of Tsukuba
• Principal Investigator: TSUCHIYA Naoyuki 筑波大学, 医学医療系, 教授 (60231437)
• Co-Investigator(Renkei-kenkyūsha): FURUKAWA Hiroshi 国立病院機構相模原病院, 臨床研究センター, 室長 (00372293)
• Project Period (FY): 2010-04-01 – 2014-03-31
• Keywords: 膠原病学 / 疾患感受性遺伝子 / 遺伝子多型 / 免疫遺伝 / ゲノム薬理学 / HLA

Research Abstract

This study aimed at finding polymorphisms associated with susceptibility to autoimmune rheumatic diseases, as well as with clinical characteristics and adverse reaction to drugs, in the Japanese population. Association of TLR7 with systemic lupus erythematosus (SLE) and SPP1 with rheumatoid arthritis (RA) was identified through international multicenter collaboration. Association of IRF2, PHRF1-IRF7 with SLE, UBE2L3 with systemic sclerosis, and IRF5 with myeloperoxidase-antineutrophil cytoplasmic antibody-associated vasculitis was detected through collaboration with national rheumatology centers. In addition, HLA-DRB1*13:02 and DRB1*14:03 were found to be protective against SLE. With respect to adverse reactions to drugs, HLA-A*31:01 was found to be associated with methotrexate associated interstitial lung disease in RA. These results will provide valuable information for the establishment of genome medicine for autoimmune rheumatic diseases in Japan.

Research Products

• [Journal Article] Human leukocyte antigens and systemic lupus erythematosus : A protective role for the HLA-DR6 alleles DRB1*13:02 and *14:03 (2014)
  • Author(s): Furukawa H, Kawasaki A, Oka S, Ito I, Shimada K, Sugii S, Hashimoto A, Komiya A, Fukui N, Kondo Y, Ito S, Hayashi T, Matsumoto I, Kusaoi M, Amano H, Nagai T, Hirohata S, Setoguchi K, Kono H, Okamoto A, Chiba N, Suematsu E, Katayama M, Migita K, Suda A, Ohno S, Hashimoto H, Takasaki Y, Sumida T, Nagaoka S, Tsuchiya N, Tohma S
  • Journal Title: PLoS One Volume: 9 Pages: e87792
  • DOI: 10.1371/journal.pone.0087792
  • Peer Reviewed
• [Journal Article] Identification of secreted phosphoprotein 1 gene as a new rheumatoid arthritis susceptibility gene (2014)
  • Author(s): Gazal S, Sacre K, Allanore Y, Teruel M, Goodall AH (The CARDIOGENICS consortium), Tohma S, Alfredsson L, Okada Y, Xie G, Constantin A, Balsa A, Kawasaki A, NIicaise P, Amos C, Rodriguez-Rodriguez L, Chioccia G, Boileau C, Zhang J, Vittecoq O, Barnetche T, Gonzalez-Gay MA, Furukawa H, Cantagrel A, Le Loet X, Sumida T, Hurtado-Nedelec M, Richez C, Chollet-Martin S, Schaeverbeke T, Combe B, Khoriaty L, Coustet B, El-Benna J, Siminovitch K, Plenge R, Padyukov L, Martin J, Tsuchiya N, Dieude P
  • Journal Title: Ann Rheum Dis Volume: (Published Online First)
  • DOI: 10.1136/annrheumdis-2013-204581
  • Peer Reviewed
• [Journal Article] Association of IRF5 polymorphism with MPO-ANCA positive vasculitis in a Japanese population (2013)
  • Author(s): Kawasaki A, Inoue N, Ajimi C, Sada K, Kobayashi S, Yamada H, Furukawa H, Sumida T, Tohma S, Miyasaka N, Matsuo S, Ozaki S, Hashimoto H, Makino H, Harigai M, Tsuchiya N
  • Journal Title: Genes Immun Volume: 14 Pages: 527-529
  • DOI: 10.1038/gene.2013.45
  • Peer Reviewed
• [Journal Article] Epistatic interaction between BANK1 and BLK in rheumatoid arthritis : results from a large trans-ethnic meta-analysis (2013)
  • Author(s): Genin E, Coustet B, Allanore Y, Ito I, Teruel M, Constantin A, Schaeverbeke T, Ruyssens-Witran A, Tohma S, Cantagrel A, Vittecoq O, Barnetche T, Le Loët X, Fardellone P, Furukawa H, Meyer O, Chiocchia G, Tsuchiya N, Martin J, Dieudé P
  • Journal Title: PLoS One Volume: 8 Pages: e61044
  • DOI: 10.1371/journal.pone.0061044
  • Peer Reviewed
• [Journal Article] Association of a single nucleotide polymorphism in the SH2D1A intronic region with systemic lupus erythematosus (2013)
  • Author(s): Furukawa H, Kawasaki A, Oka S, Shimada K, Nakayama H, Matsui T, Ikenaka T, Hashimoto A, Okazaki Y, Takaoka H, Futami H, Komiya A, Kondo Y, Ito S, Hayashi T, Matsumoto I, Kusaoi M, Takasaki Y, Nagai T, Hirohata S, Setoguchi K, Nagaoka S, Kono H, Okamoto A, Fukui N, Hashimoto H, Sumida T, Ono M, Tsuchiya N, Tohma S.
  • Journal Title: Lupus Volume: 22 Pages: 497-503
  • DOI: 10.1177/0961203313479421
  • Peer Reviewed
• [Journal Article] PLD4 as a novel susceptibility gene for systemic sclerosis in a Japanese population (2013)
  • Author(s): Terao C, Ohmura K, Kawaguchi Y, Nishimoto T, Kawasaki A, Takehara K, Furukawa H, Kochi Y, Ota Y, Ikari K, Sato S, Tohma S, Yamada R, Yamamoto K, Kubo M, Yamanaka H, Kuwana M, Tsuchiya N, Matsuda F, Mimori T
  • Journal Title: Arthritis Rheum Volume: 65 Pages: 472-480
  • DOI: 10.1002/art.37777
  • Peer Reviewed
• [Journal Article] Genome, epigenome and transcriptome analyses of a pair of monozygotic twins discordant for systemic lupus eythematosus (2013)
  • Author(s): Furukawa H, Oka S, Matsui T, Hashimoto A, Arinuma Y, Komiya A, Fukui N, Tsuchiya N, Tohma S
  • Journal Title: Hum Immunol Volume: 74 Pages: 170-175
  • DOI: 10.1016/j.humimm.2012.11.007
  • Peer Reviewed
• [Journal Article] Association of increased frequencies of HLA-DPB1*05 : 01 with the presence of anti-Ro/SS-A and anti-La/SS-B antibodies in Japanese rheumatoid arthritis and systemic lupus erythematosuspatients (2013)
  • Author(s): Furukawa H, Oka S, Shimada K, Sugii S, Hashimoto A, Komiya A, Fukui N, Miyashita T, Migita K, Suda A, Nagaoka S, Tsuchiya N, Tohma S
  • Journal Title: PLoS One Volume: 8 Pages: e53910
  • DOI: 10.1371/journal.pone.0053910
  • Peer Reviewed
• [Journal Article] HLA-A*31 : 01 and methotrexateinduced interstitial lung disease in Japanese rheumatoid arthritis patients: a multi-drug hypersensitivity marker? (2013)
  • Author(s): Furukawa H, Oka S, Shimada K, Rheumatoid Arthritis associated Interstitial Lung Disease (RA-ILD) Study Consortium, Tsuchiya N, Tohma S
  • Journal Title: Ann Rheum Dis Volume: 72 Pages: 153-155
  • DOI: 10.1136/annrheumdis-2012-201944
  • Peer Reviewed
• [Journal Article] Genetics of ANCA-associated vasculitis in Japan - a role for HLA-DRB1*09 : 01 haplotype (2013)
  • Author(s): Tsuchiya N
  • Journal Title: Clin Exp Nephrol Volume: 17 Pages: 628-630
  • DOI: 10.1007/s10157-012-0691-6
  • Peer Reviewed
• [Journal Article] Association of PHRF1-IRF7 region polymorphism with clinical phenotypes of systemic lupus erythematosus : an association study in a Japanese population (2012)
  • Author(s): Kawasaki A, Furukawa H, Kondo Y, Ito S, Hayashi T, Kusaoi M, Matsumoto I, Tohma S, Takasaki Y, Hashimoto H, Sumida T, Tsuchiya N
  • Journal Title: Lupus Volume: 21 Pages: 890-895
  • DOI: 10.1177/0961203312439333
  • Peer Reviewed
• [Journal Article] Association of human leukocyte antigen with interstitial lung disease in rheumatoid arthritis : A protective role for shared epitope (2012)
  • Author(s): Furukawa H, Oka S, Shimada K, Sugii S, Ohashi J, Matsui T, Ikenaka T, Nakayama H, Hashimoto A, Takaoka H, Arinuma Y, Okazaki Y, Futami H, Komiya A, Fukui N, Nakamura T, Migita K, Suda A, Nagaoka S, Tsuchiya N, Tohma S
  • Journal Title: PLoS One Volume: 7 Pages: e33133
  • DOI: 10.1371/journal.pone.0033133
  • Peer Reviewed
• [Journal Article] Association of UBE2L3 polymorphisms with diffuse cutaneous systemic sclerosis in a Japanese population (2012)
  • Author(s): Hasebe N, Kawasaki A, Ito I, Kawamoto M, Hasegawa M, Fujimoto M, Furukawa H, Tohma S, Sumida T, Takehara K, Sato S, Kawaguchi Y, Tsuchiya N
  • Journal Title: Ann Rheum Dis Volume: 71 Pages: 1259-1260
  • DOI: 10.1136/annrheumdis-2011-201091
  • Peer Reviewed
• [Journal Article] Effects of APRIL (TNFSF13) polymorphisms and splicing isoforms on the secretion of soluble APRIL (2012)
  • Author(s): Furuya T, Koga M, Hikami K, Kawasaki A, Tsuchiya N
  • Journal Title: Mod Rheumatol Volume: 22 Pages: 541-549
  • DOI: 10.1007/s10165-011-0539-z
  • Peer Reviewed
• [Journal Article] Association of TNFAIP3 interacting protein 1, TNIP1 with systemic lupus erythematosus in a Japanese population : a case-control association study (2012)
  • Author(s): Kawasaki A, Ito S, Furukawa H, Hayashi T, Goto D, Matsumoto I, Kusaoi M, Ohashi J, Graham RR, Matsuta K, Behrens TW, Tohma S, Takasaki Y, Hashimoto H, Sumida T, Tsuchiya N
  • Journal Title: Arthritis Res Ther Volume: 12 Pages: R174
  • DOI: 10.1186/ar3134
  • Peer Reviewed
• [Journal Article] Cumulative association of eight susceptibility genes with systemic lupus erythematosus in a Japanese female population (2011)
  • Author(s): Koga M, Kawasaki A, Ito I, Furuya T, Ohashi J, Kyogoku C, Ito S, Hayashi T, Matsumoto I, Kusaoi M, Takasaki Y, Hashimoto H, Sumida T, Tsuchiya N
  • Journal Title: J Hum Genet Volume: 56 Pages: 503-507
  • DOI: 10.1038/jhg.2011.49
  • Peer Reviewed
• [Journal Article] TLR7 single-nucleotide polymorphisms in the 3' untranslated region and intron 2 independently contribute to systemic lupus erythematosus in Japanese women : a case-control association study (2011)
  • Author(s): Kawasaki A, Furukawa H, Kondo Y, Ito S, Hayashi T, Kusaoi M, Matsumoto I, Tohma S, Takasaki Y, Hashimoto H, Sumida T, Tsuchiya N
  • Journal Title: Arthritis Res Ther Volume: 13 Pages: R41
  • DOI: 10.1186/ar3277
  • Peer Reviewed
• [Journal Article] Association of a functional polymorphism in the 3' untranslated region of SPI1 with systemic lupus erythematosus (2011)
  • Author(s): Hikami K, Kawasaki A, Ito I, Koga M, Ito S, Hayashi T, Matsumoto I, Tsutsumi A, Kusaoi M, Takasaki Y, Hashimoto H, Arinami T, Sumida T, Tsuchiya N
  • Journal Title: Arthritis Rheum Volume: 63 Pages: 755-763
  • DOI: 10.1002/art.30188
  • Peer Reviewed
• [Journal Article] Sex-specific association of X-linked Toll-like receptor 7 (TLR7) with male systemic lupus erythematosus (2010)
  • Author(s): Shen N, Fu Q, Deng Y, Qian X, Zhao J, Kaufman KM, Wu YL, Yu CY, Tang Y, Chen J-Y, Yang W, Wong M, Kawasaki A, Tsuchiya N, Sumida T, Kawaguchi Y, Howe HS, Mok MY, Bang S-Y, Liu F-L, Chang D-M, Takasaki Y, Hashimoto H, Harley JB, Guthridge JM, Grossman JM, Cantor RM, Song YW, Bae S-C, Chen S, Hahn BH, Lau YL, Tsao BP
  • Journal Title: Proc Natl Acad Sci USA Volume: 107 Pages: 15838-15843
  • DOI: 10.1073/pnas.1001337107
  • Peer Reviewed
• [Journal Article] Association of TNFAIP3 polymorphism with susceptibility to systemic lupus erythematosus in a Japanese population (2010)
  • Author(s): Kawasaki A, Ito I, Ito S, Hayashi T, Goto D, Matsumoto I, Takasaki Y, Hashimoto H, Sumida T, Tsuchiya N
  • Journal Title: J Biomed Biotechnol
  • DOI: 10.1155/2010/207578
  • Peer Reviewed
• [Journal Article] Association of the FAM167A-BLK region with systemic sclerosis (2010)
  • Author(s): Ito I, Kawaguchi K, Kawasaki A, Hasegawa M, Ohashi J, Kawamoto M, Fujimoto M, Takehara K, Sato S, Hara M, Tsuchiya N
  • Journal Title: Arthritis Rheum Volume: 62 Pages: 890-895
  • DOI: 10.1002/art.27303
  • Peer Reviewed
• [Journal Article] HLA-DRB1*08 : 02 is associated with bucillamine-induced proteinuria in Japanese rheumatoid arthritis patients
  • Author(s): Furukawa H, Oka S, Shimada K, Sugii S, Hashimoto A, Komiya A, Fukui N, Miyashita T, Migita K, Suda A, Nagaoka S, Tsuchiya N, Tohma S
  • Journal Title: Biomarker Insights Volume: (in press)
  • Peer Reviewed
• [Presentation] Association of functional polymorphisms In IRF2 with systemic lupus erythematosus (SLE) In a Japanese Population (2013)
  • Author(s): Kawasaki A, et al
  • Organizer: 2013 American College of Rheumatology Annual Scientific Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 20131026-30
• [Presentation] HLA-DRB1*08 : 02 is associated with bucillamine-induced proteinuria in Japanese rheumatoid arthritis patients: A case-control study (2013)
  • Author(s): Furukawa H, et al
  • Organizer: 2013 American College of Rheumatology Annual Scientific Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 20131026-30
• [Presentation] Genetic background of ANCA-associated vasculitis in a Japanese population : a candidate gene studystudy. (シンポジウム指定演者) (2012)
  • Author(s): Tsuchiya N, et al
  • Organizer: The Asia and Pacific Meeting of Vasculitis and ANCA Workshop
  • Place of Presentation: 東京
  • Year and Date: 20120328-31
• [Presentation] Genetic background of antineutrophil Cytoplasmic Antibody-Associated Vasculitis in a Japanese Population : association of STAT4 with myeloperoxidase antineutrophil cytoplasmic antibody-positive vasculitis (2012)
  • Author(s): Kawasaki A, et al
  • Organizer: 2012 American College of Rheumatology Annual Scientific Meeting
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2012-10-10
• [Presentation] Epistatic interaction between BANK1 and BLK in rheumatoid arthritis : Results from a large trans-ethnic meta-analysis (2012)
  • Author(s): Genin E, et al
  • Organizer: 2012 American College of Rheumatology Annual Scientific Meeting
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2012-10-10
• [Presentation] リウマチ・膠原病のゲノム解析 (2012)
  • Author(s): 土屋尚之
  • Organizer: 都立駒込病院総合カンファランス
  • Place of Presentation: 東京(特別講演)
  • Year and Date: 2012-08-29
• [Presentation] 膠原病のゲノム解析研究 (2012)
  • Author(s): 土屋尚之
  • Organizer: 第53回湘南免疫疾患カンファランス
  • Place of Presentation: 横浜(特別講演)
  • Year and Date: 2012-06-23
• [Presentation] 膠原病のゲノム解析から明らかになったことと今後の課題 (2012)
  • Author(s): 土屋尚之
  • Organizer: 第7回長崎皮膚・膠原病フォーラム
  • Place of Presentation: 長崎(特別講演)
  • Year and Date: 2012-06-14
• [Presentation] 膠原病の候補遺伝子解析(シンポジウム指定演者) (2012)
  • Author(s): 土屋尚之
  • Organizer: 第56回日本リウマチ学会総会・学術集会
  • Place of Presentation: グランドプリンスホテル新高輪, 東京
  • Year and Date: 2012-04-27
• [Presentation] Association of TNFAIP3 and TNIP1 SNPs with systemic lupus erythematosus in a Japanese population (2010)
  • Author(s): Kawasaki A, et al
  • Organizer: 9th International Congress on Systemic Lupus Erythematosus
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 20100624-27
• [Presentation] An association study of 8p23.1 region encoding BLK, FAM167A, C8orf12 and XKR6 with systemic lupus erythematosus in Japanese. (2010)
  • Author(s): Ito I, et al
  • Organizer: 9th International Congress on Systemic Lupus Erythematosus
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 20100624-27
• [Book] 環境因子と遺伝因子.ANCA 関連血管炎の診療ガイドライン(2014 年改訂版)(厚生労働省 難治性疾患克服研究事業 槇野博史,松尾清一編 (2014)
  • Author(s): 土屋尚之
  • Total Pages: 10-12
• [Book] 全身性強皮症の疾患感受性遺伝子にはどのようなものがあるか.皮膚科臨床アセット7「皮膚科膠原病のすべて」(古江増隆,佐藤伸一編) (2011)
  • Author(s): 土屋尚之
  • Total Pages: 161-165
  • Publisher: 中山書店
• [Book] 全身性エリテマトーデスの疾患感受性遺伝子にはどのようなものがあるか.皮膚科臨床アセット7「皮膚科膠原病のすべて」(古江増隆,佐藤伸一編) (2011)
  • Author(s): 土屋尚之
  • Total Pages: 63-67
  • Publisher: 中山書店
• [Book] 病因.最新医学別冊「新しい診断と治療のABC 67全身性エリテマトーデス」(竹内勤編) (2010)
  • Author(s): 土屋尚之
  • Total Pages: 58-71
  • Publisher: 最新医学社
• [Remarks]
  • URL: http://www.md.tsukuba.ac.jp/community-med/publicmd/GE/