| Project/Area Number |
17K09967
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Collagenous pathology/Allergology
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| Research Institution | University of Tsukuba |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
針谷 正祥 東京女子医科大学, 医学部, 教授 (20238207)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2017: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
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| Keywords | HLA-class II / 多型 / 疾患感受性 / 疾患抵抗性 / ANCA関連血管炎 / HLA class II / 疾患感受性遺伝子 / 疾患抵抗性遺伝子 / 一塩基バリアント / eQTL / 主要組織適合性遺伝子複合体 / HLA / 疾患関連遺伝子 / シークエンス / 膠原病 / ゲノム |
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| Outline of Final Research Achievements |
We previously identified association of HLA-DRB1*13:02 with protection against, and that of HLA-DRB1*09:01-DQB1*03:03 haplotype with susceptibility to, multiple autoimmune diseases including MPO-ANCA positive vasculitis in the Japanese population. In this study, we made an attempt to identify the causal variants which can account for the genetic association of these haplotypes. As for the protective association, the role for HLA-DRB1*13:02 itself was supported. With respect to the predispositional association, novel variants located in the upstream region of HLA-DRA and are in linkage disequilibrium with DRB1*09:01 were suggested to play an independent role. These variants were shown to be associated with expression level of HLA-DQA1 and DQB1 by eQTL analysis. These results imply that multiple variants with an independent contribution are carried by the DRB1*09:01 haplotype, some of which may be associated by a mechanism other than the antigenic peptide specificity.
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| Academic Significance and Societal Importance of the Research Achievements |
HLAは多くの免疫関連疾患において重要な疾患感受性あるいは抵抗性遺伝子であるが、広範囲にわたる連鎖不平衡のために、病因的意義を有するバリアントが特定されておらず、分子機構は未解明である。本研究では、日本人集団においてANCA関連血管炎をはじめとする複数の免疫疾患の疾患抵抗性、疾患感受性にそれぞれ関連するHLA-DRB1*13:02、DRB1*09:01-DQB1*03:03ハプロタイプにおいて、病因的であるバリアントを探索した。これは、学術的にはHLAと疾患の関連の分子機構の解明に、社会的には日本人集団において有用性の高い複数の免疫疾患に対する創薬の分子標的の同定につながる知見と考えられる。
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