The important roles of a common protective allele HLA-DRB1*13:02 in collagen diseases.

• Project/Area Number: 18K08402
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Tokyo National Hospital (Clinical research) (2019-2020); University of Tsukuba (2018)
• Principal Investigator: Hiroshi Furukawa 独立行政法人国立病院機構東京病院(臨床研究部), 臨床研究部, 臨床研究部長 (00372293)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 病因・病態 / HLA / 遺伝子解析 / 疾患発症抑制遺伝子

Outline of Final Research Achievements

DRB1*13:02 allele is protective against systemic autoimmune diseases including systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). The protective effect of DRB1*13:02 was investigated in mixed connective tissue disease and polymyalgia rheumatica. DRB1*13:02 was protective against mixed connective tissue disease and DR6 (DRB1*13, DRB1*14) serological group was protective against polymyalgia rheumatica.
Transgenic mouse of DRB1*13:02 was generated in MRL/Mp.Faslpr and C57BL/6. The protein of DRB1*13:02 was confirmed in C57BL/6, but not in MRL/Mp.Faslpr. Pristane-induced lupus model was developed in transgenic mouse of DRB1*13:02 in C57BL/6. However, al the mice were dead before the evaluation.

Academic Significance and Societal Importance of the Research Achievements

HLAのアレルHLA-DRB1*13:02が膠原病やその類縁疾患の発症に共通して抑制的に関連することを、日本人集団での関連解析で明らかにしてきた。この研究では、MCTDの発症にDRB1*13:02 は負の関連を示し、PMRの発症にDR6(DRB1*13, DRB1*14)は負の関連を示し、この関連は確かなものと考えられた。DRB1*13:02トランスジェニックマウスを作成し、DR13分子が膠原病発症を抑制する可能性を検証しようとしたが、叶わなかった。DR13分子が膠原病の発症を抑制する機序を明らかにすることはできなかった。

Research Products

• [Journal Article] Genetic risk factors for autoimmune hepatitis: implications for phenotypic heterogeneity and biomarkers for drug response. (2021)
  • Author(s): Higuchi T, Oka S, Furukawa H, Tohma S, Yatsuhashi H, Migita K.
  • Journal Title: Hum Genomics Volume: 15 Issue: 1 Pages: 6-6
  • DOI: 10.1186/s40246-020-00301-4
  • Peer Reviewed / Open Access
• [Journal Article] The attenuation of insulin-like growth factor signaling may be responsible for relative reduction in matrix synthesis in degenerated areas of osteoarthritic cartilage (2021)
  • Author(s): Tanaka N, Tsuno H, Ohashi S, Iwasawa M, Furukawa H, Kato T, Fukui N.
  • Journal Title: BMC Musculoskelet Disord . Volume: 22(1) Issue: 1 Pages: 231-231
  • DOI: 10.1186/s12891-021-04096-w
  • Peer Reviewed / Open Access
• [Journal Article] Serum Metabolomic Profiling in Rheumatoid Arthritis Patients With Interstitial Lung Disease: A Case-Control Study (2020)
  • Author(s): Furukawa H, Oka S, Shimada K, Okamoto A, Hashimoto A, Komiya A, Saisho K, Yoshikawa N, Katayama M, Matsui T, Fukui N, Migita K, Tohma S.
  • Journal Title: Front Med (Lausanne) Volume: 17 Pages: 599794-599794
  • DOI: 10.3389/fmed.2020.599794
  • Peer Reviewed / Open Access
• [Journal Article] Association of functional (GA)n microsatellite polymorphism in the FLI1 gene with susceptibility to human systemic sclerosis. (2020)
  • Author(s): Yamashita K, Kawasaki A, Matsushita T, Furukawa H, Kondo Y, Okiyama N, Nagaoka S, Shimada K, Sugii S, Katayama M, Hirohata H, Okamoto A, Chiba N, Suematsu E, Setoguchi K, Migita K, Sumida T, Tohma S, Hasegawa M, Hamaguchi Y, Sato S, Kawaguchi Y, Takehara K, *Tsuchiya N.
  • Journal Title: Rheumatology (Oxford). Volume: 59 Issue: 11 Pages: 3553-3562
  • DOI: 10.1093/rheumatology/keaa306
  • Peer Reviewed
• [Journal Article] Association of HLA-DRB1 genotype with younger age onset and elder age onset rheumatoid arthritis in Japanese populations. (2019)
  • Author(s): Oka S, Furukawa H, Shimada K, Hashimoto A, Komiya A, Tsunoda S, Saisho K, Tsuchiya N, Katayama M, Shinohara S, Matsui T, Fukui N, Sano H, Migita K, Tohma S.
  • Journal Title: Medicine (Baltimore). Volume: 98(48) Issue: 48 Pages: 18218-18218
  • DOI: 10.1097/md.0000000000018218
  • NAID: 120007132911
  • Peer Reviewed / Open Access
• [Journal Article] Human leukocyte antigen in Japanese patients with idiopathic inflammatory myopathy (2019)
  • Author(s): Furukawa H, Oka S, Kawasaki A, Hidaka M, Shimada K, Kondo Y, Ihata A, Matsushita T, Matsumoto T, Hashimoto A, Matsumoto I, Komiya A, Kobayashi K, Osada A, Katayama M, Okamoto A, Setoguchi K, Kono H, Hamaguchi Y, Matsui T, Fukui N, Tamura H, Takehara K, Nagaoka S, Sugii S, Sumida T, Tsuchiya N, Tohma S.
  • Journal Title: Mod Rheumatol. Volume: 30 Issue: 4 Pages: 696
  • DOI: 10.1080/14397595.2019.1637593
  • URL: https://pure.teikyo.jp/en/publications/2cc3a0de-f27a-4e97-95d4-02f0b4174ce2
  • Peer Reviewed
• [Journal Article] HLA-DQB1 DPB1 alleles in Japanese patients with Adult-onset Still's disease. (2019)
  • Author(s): Fujita Y, Furukawa H, Asano T, Sato S, Yashiro M, Kobayashi H, Watanabe H, Suzuki E, Koga T, Shimizu T, Ueki Y, Eguchi K, Tsuchiya N, Kawakami A, Migita K.
  • Journal Title: Mod Rheumatol. Volume: in press Issue: 5 Pages: 843-847
  • DOI: 10.1080/14397595.2018.1514999
  • Peer Reviewed
• [Journal Article] Independent association of HLA-DPB1*02:01 with rheumatoid arthritis in Japanese populations. (2018)
  • Author(s): Furukawa H, Oka S, Shimada K, Hashimoto A, Komiya A, Tsunoda S, Suda A, Ito S, Saisho K, Katayama M, Shinohara S, Sato T, Nagatani K, Minota S, Matsui T, Fukui N, Sugii S, Sano H, Migita K, Nagaoka S, Tohma S.
  • Journal Title: PLOS ONE Volume: 13 Issue: 9 Pages: e0204459-e0204459
  • DOI: 10.1371/journal.pone.0204459
  • NAID: 120007128212
  • Peer Reviewed / Open Access
• [Presentation] 関節リウマチ関連間質性肺病変に関連する自己抗体 (2020)
  • Author(s): 岡笑美,古川宏,島田浩太 岡本享,橋本篤,小宮明子,税所幸一郎,吉川教恵,片山雅夫,松井利浩,福井尚志,右田清志 當間重人:
  • Organizer: 第74回国立病院総合医学会
• [Presentation] 変形性関節症における滑膜病変 (2020)
  • Author(s): 福井尚志,田中伸帆津野宏隆,大橋暁,岩澤三康,古川宏:
  • Organizer: 第64回日本リウマチ学会
• [Presentation] リウマチ関連リンパ増殖性疾患の多施設共同研究による病理学的解析 (2020)
  • Author(s): 星田義彦,大島至郎,佐伯行彦,宮村知也,片山雅夫,大島久二,比嘉慎二,吉川教恵,満尾晶子,岡本享,千葉実行,八木田正人,角田慎一郎,杉山隆夫,井畑淳,長岡章平,吉原良祐,瀬戸口京吾,松井聖,市川健司,古川宏,當間重人:
  • Organizer: 第64回日本リウマチ学会
• [Presentation] 関節リウマチ関連間質性肺病変に関連する自己抗体 (2020)
  • Author(s): 岡笑美,古川宏,島田浩太 岡本享,橋本篤,小宮明子,税所幸一郎,吉川教恵,片山雅夫,松井利浩,福井尚志,右田清志,當間重人
  • Organizer: 第64回日本リウマチ学会
• [Presentation] HLAクラスIIと日本人若年発症および高齢発症関節リウマチとの関連 (2019)
  • Author(s): 岡笑美,古川宏,島田浩太,橋本篤,小宮明子,角田慎一郎,税所幸一郎,土屋尚之,片山雅夫,篠原聡,松井利浩,福井尚志,佐野統,右田清志,當間重人
  • Organizer: 第73回国立病院総合医学会
• [Presentation] 若年発症および高齢発症関節リウマチとDRB1遺伝型との関連 (2019)
  • Author(s): 岡笑美,古川宏,島田浩太,橋本篤,小宮明子,角田慎一郎,税所幸一郎,土屋尚之,片山雅夫,篠原聡,松井利浩,福井尚志,佐野統,右田清志,當間重人
  • Organizer: 第63回日本リウマチ学会
• [Presentation] Ninjaネットワークを利用した関節リウマチ関連間質性肺病変のバイオマーカー探索 (2018)
  • Author(s): 古川宏
  • Organizer: 第72回国立病院総合医学会
  • Invited
• [Presentation] ANCA関連血管炎における間質性肺疾患とHLA ClassIIアリルの関連 (2018)
  • Author(s): 川崎綾,平野史生,佐田憲映,小林茂人,山田秀裕,古川宏,長坂憲治,杉原毅彦,山縣邦弘,住田孝之,當間重人,尾崎承一,橋本博史,槇野博史,有村義宏,針谷正祥,土屋尚之
  • Organizer: 第63回日本人類遺伝学会大会
• [Presentation] 自己免疫性肝炎とHLA (2018)
  • Author(s): 岡笑美,古川宏,川崎綾,當間重人,土屋尚之,右田清志
  • Organizer: 第62回日本リウマチ学会
• [Presentation] 成人発症スティル病患者におけるHLA-DRB1アリルの感受性と臨床症状への影響 (2018)
  • Author(s): 浅野智之,古川宏,古谷牧子,佐藤秀三,小林浩子,渡辺浩志,古賀智裕,川上純,右田清志
  • Organizer: 第62回日本リウマチ学会
• [Presentation] 日本人ANCA関連血管炎のHLA-classII:ヨーロッパ系集団との比較 (2018)
  • Author(s): 川崎綾,平野史生,佐田憲映,小林茂人,山田秀裕,古川宏,長坂憲治,杉原毅彦,山縣邦弘,住田孝之,當間重人,尾崎承一,橋本博史,槇野博史,有村義宏,針谷正祥,土屋尚之
  • Organizer: 第62回日本リウマチ学会
• [Presentation] 成人発症スティル病の遺伝的要因の検討 (2018)
  • Author(s): 浅野智之,古川宏,屋代牧子,佐藤秀三,小林浩子,渡辺浩志,古賀智裕,江口勝美,川上純,右田清志
  • Organizer: 第115回日本内科学会講演会