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 |
Section | 一般 |
Review Section |
Basic Section 53020:Cardiology-related
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Research Institution | Tokyo Medical and Dental University |
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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Project Status |
Completed (Fiscal Year 2020)
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Budget Amount *help |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2019: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2018: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
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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 / 酸化ストレス / 個別化医療 / 1塩基多型 / 全ゲノム関連解析 / 全エクソン関連解析 |
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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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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Report
(4 results)
Research Products
(22 results)
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[Journal Article] Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells2020
Author(s)
Higashijima Y, Matsui Y, Shimamura T, Nakaki R, Nagai N, Tsutsumi S, Abe Y, Link VM, Osaka M, Yoshida M, Watanabe R, Tanaka T, Taguchi A, Miura M, Ruan X, Li G, Inoue T, Nangaku M, Kimura H, Furukawa T, Aburatani H, Wada Y, Ruan Y, Glass CK, Kanki Y
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Journal Title
The EMBO Journal
Volume: 39
Issue: 7
Pages: 1-1
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Mutant KCNJ3 and KCNJ5 potassium channels as novel molecular targets in bradyarrhythmias and atrial fibrillation.2019
Author(s)
Yamada N, Asano Y, Fujita M, Yamazaki S, Inanobe A, Matsuura N, Kobayashi H, Ohno S, Ebana Y, Tsukamoto O, Ishino S, Takuwa A, Kioka H, Yamashita T, Hashimoto N, Zankov DP, Shimizu A, Asakura M, Asanuma H, Kato H, Nishida Y, Miyashita Y, Shinomiya H, Naiki N, Hayashi K, Makiyama T, Ogita H, et al.
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Journal Title
Circulation
Volume: In press
Issue: 18
Pages: 2157-2169
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Combined Analysis of Human and Experimental Murine Samples Identified Novel Circulating MicroRNAs as Biomarkers for Atrial Fibrillation2018
Author(s)
Natsume Y, Oaku K, Takahashi K, Nakamura W, Oono A, Hamada S, Yamazoe M, Ihara K, Sasaki T, Goya M, Hirao K, Furukawa T, Sasano T.
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Journal Title
Circulation Journal
Volume: 82
Issue: 4
Pages: 965-973
DOI
NAID
ISSN
1346-9843, 1347-4820
Related Report
Peer Reviewed / Open Access
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[Presentation] Disease modeling using iPS cells2018
Author(s)
Furukawa T, Okata S, Yuasa S, Suzuki T, Makita N, Kurokawa J, Egashira T, Yamakawa H, Seki T, Aizawa T, Hashimoto H, Kuroda Y, Tanaka A, Yae K, Murata M, Aiba T, Shimizu W, Horie M, Kodama I, Ogawa S, Fukuda K
Organizer
第78回日本循環器学会
Related Report
Invited
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[Presentation] Impact of SNP on IL6R (rs7514452) for age at onset of atrial fibrillation2018
Author(s)
Sato Y, Satoh A, Nitta J, Honda Y, Kuroda S, Sekigawa M, Kanoh M, Suzuki M, Inaba O, Muramatsu K, Yamato T, Matsumura Y, Asakawa K, Ebana Y, Furukawa T, Hirao K, Isobe M
Organizer
第78回日本循環器学会
Related Report
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[Presentation] Effect of SNP on 9q22 (rs6479562) on the progression from paroxysmal atrial fibrillation to persistent atrial fibrillation2018
Author(s)
Sekigawa M, Satoh A, Nitta J, Sato Y, Honda Y, Kuroda S, Kanoh M, Suzuki M, Inaba O, Muramatsu K, Yamato T, Matsumura Y, Asakawa K, Ebana Y, Furukawa T, Hirao K, Isobe M
Organizer
第78回日本循環器学会
Related Report
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