2004 Fiscal Year Final Research Report Summary
Studies on the causative disease gene in autoimmunity and rheumatoid arthritis
| Project/Area Number |
13204059
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Kobe University |
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Principal Investigator |
SHIOZAWA Shunichi Kobe University, School of Medicine, Professor, 医学部, 教授 (40154166)
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| Co-Investigator(Kenkyū-buntansha) |
ISHIKAWA Hitoshi Kobe University, School of Medicine, Professor, 医学部, 教授 (30107958)
MIURA Yasushi Kobe University, School of Medicine, Associate Professor, 医学部, 助教授 (60346244)
HASHIRAMOTO Akira Kobe University, School of Medicine, Associate Professor, 医学部, 助教授 (80346246)
KOMAI Koichiro Kobe University, School of Medicine, Assistant Lecturer, 医学部, 助手 (40304117)
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| Project Period (FY) |
2000 – 2004
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| Keywords | rheumatoid arthritis (RA) / death receptor 3 (DR3) / disease gene |
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| Research Abstract |
BACKGROUND
while the defect in apoptosis causes characteristic systemic autoimmunity in mice, the contribution of apoptosis to human systemic autoimmunity is unclear.
The present study was designed to elucidate the contribution of death receptor 3 (DR3) gene, a member of apoptosis-inducing TNF receptor gene family including Fas, to the pathogenesis of RA.
METHODS
Mutation was identified by sequencing death receptor 3(DR3) genome and assessed in relation to gene expression, molecular assembly, apoptosis induction and the prevalence of RA in 2,480 patients with RA and 1,270 healthy controls in Japan and Korea.
RESULTS
We identified a variant of DR3 gene, a family of apoptosis-inducing Fas gene, containing 4 single nucleotide polymorphisms (SNPs) and one locus of a 14 nucleotide deletion within exon 5 and intron 5 in patients with rheumatoid arthritis (RA), in which g.2590 A>T mutation resulted in insertion of a portion of intron 5 into the coding sequence to generate premature stop codon. Truncated product DR3 molecule lacking death domain assembled with authentic DR3 to inhibit ligand-induced apoptosis in the lymphocytes of patients with mutation. The variant existed in 3.19% of patients with RA among Japanese oriental genealogy with odds ratio 13.9 (p=1.2x10^<-10>).
CONCLUSIONS
Variant DR3 of relatively low frequency generates truncated DR3 molecule lacking death domain, which assembled with authentic DR3 molecule to inhibit apoptosis and predisposes to RA.
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[Journal Article] Heat shock protein 90 is required for increased DNA binding activity of activator protein-1, a heterodimer of Fos/JunD, in rheumatoid synovial cells under inflammatory stimuli.2005
Author(s)
Murata M, Miura Y, Hashiramoto A, Kitamura H, Kawasaki H, Shiozawa K, Yoshiya S, Baba H, Chihara K, Shiozawa S.
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Journal Title
Int J Mol Med 15
Pages: 645-653
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Whole genome association study of rheumatoid arthritis using 27039 microsatellites.2005
Author(s)
Tamiya G, Shinya M, Imanishi T, Ikuta T, Makino S, Okamoto K, Furugaki K, Matsumoto T, Mano S, Ando S, Nozaki Y, Yukawa W, Nakashige R, Yamaguchi D, Ishibashi H, Yonekura M, Yoshikawa Y, Fujimoto K, Oka A, Chiku S, Linsen SEV, Giphart MJ, Hoshina Y, Suzuki Y, Hotta T, Mochida J, Minezaki, Komai K, Shiozawa S, et al.
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Journal Title
Human Mol Genet 14
Pages: 2305-2321
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Nonaka Y, Nakagawa K, Okano T, Ohta M, Inouye K. Metabolism of 26, 26, 26, 27, 27, 27-F6-1a, 25-dihydroxyvitamin D3 by CYP24 : Species-based difference between humans and rats.2003
Author(s)
Sakaki T
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Journal Title
Biochem Pharmacol 65巻
Pages: 1957-1965
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Metabolism of 26, 26, 26, 27, 27, 27-F6-1a, 25-dihydroxyvitamin D3 by CYP24 : Species-based difference between humans and rats.2003
Author(s)
Sakaki T, Sawada N, Abe D, Komai K, Shiozawa S, Nonaka Y, Nakagawa K, Okano T, Ohta M, Inouye K.
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Journal Title
Biochem Pharmacol 65
Pages: 1957-1965
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Human wee 1 kinase is directly transactivated by and increased in association with c-Fos/AP-1 : Rheumatoid synovial cells overexpressing these genes go into aberrant mitosis.2003
Author(s)
Kawasaki H, Komai K, Nakamura M, Yamamoto E, OuYang Z, Nakashima T, Hashiramoto A, Shiozawa K, Ishikawa H, Kurosaka M, Shiozawa S.
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Journal Title
Oncogene 22
Pages: 6839-6844
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Spontaneous, cytokine regulated c-fos gene expression in rheumatoid synovial cells resistance to cytokine Stimulation when the c-fos gene is overexpressed.2000
Author(s)
Shimizu K, Kawasaki H, Morisawa T, Nakamura M, Yamamoto E, Yoshikawa N, Doita M, Shiozawa K, Yonehara S, Chihara K, Shiozawa S.
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Journal Title
Ann Rheum Dis 59(8)
Pages: 636-640
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The promoter region of death receptor 3 (DR3) is specifically hypermethylated in rheumatoid synovial cells.
Author(s)
Takami N, Osawa K, Miura Y, Komai K, Taniguchi M, Shiraishi M, Sato K, Iguchi T, Shiozawa K, Hashiramoto A, Shiozawa S.
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Journal Title
Arthritis Rheum (in press.)
Description
「研究成果報告書概要(欧文)」より
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