2020 Fiscal Year Final Research Report
Search for the pathogenesis and drug target of atrial fibrillation based on ExWAS
| Project/Area Number |
18H02803
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 53020:Cardiology-related
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
竹内 純 東京医科歯科大学, 難治疾患研究所, 准教授 (10451999)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Keywords | 心房細動 / 全エクソン相関解析 / 自律神経 / マクロファージ / 炎症 |
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| Outline of Final Research Achievements |
Whole-exon association analysis (ExWAS) of atrial fibrillation (AF) yeiled two
rare single nucleotide polymorphisms (SNPs) with high odds ratios and amino acid substitutions. Then, we carried out in vitro analysis with cultured cells and in vivo with genome-edited mice. We showed that the AF-sensitive sall 3 SNP, which was identified in AF ExWAS performed in the elderly poses a risk of developing AF by causing abnormal differentiation of the autonomic nerves into sympathetic and parasympathetic. In terms of the AF-sensitive SNP of Tks5, which was identified in ExWAS in young people, is at risk of developing AF by enhancing the migration and infiltration of macrophage, resulting in induction of inflammation.
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| Free Research Field |
循環器内科学
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| Academic Significance and Societal Importance of the Research Achievements |
心房細動は最も多い不整脈であり（患者数約100万人）、高頻度に脳卒中（心原性脳塞栓）を合併し、寝たきりの原因となるため、その治療が喫緊の社会問題となっている。全ゲノム関連解析では、1塩基多型が遺伝子外に存在することが多く、疾患との関連が低いことで創薬シーズを同定するに至っていない。全エクソン関連解析を用いることにより、疾患との関連が高く、アミノ酸置換を有する変異を2つ同定した。その機能解析から、これまで知られていなかった心房細動の新たな病態発現機構、創薬シーズを同定でき、心房細動の新たな治療戦略に役立つことが期待できる。
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