| Project/Area Number |
18K15863
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53020:Cardiology-related
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| Research Institution | Juntendo University |
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Principal Investigator |
Okazaki Atsuko 順天堂大学, 医学(系)研究科(研究院), 准教授 (70761691)
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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 |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2018: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
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| Keywords | ミトコンドリア病 / 遺伝統計学 / 心筋症 / 網羅的遺伝子解析 / ミトコンドリア心筋症 / ミトコンドリアDNA / 遺伝性心筋症 / 遺伝統計 / ヘテロプラスミー率 / digital PCR / ゲノム解析 / 原因遺伝子探索 / バイオインフォマティクス / エクソーム解析 / 疾患変異 / 染色体構造異常 / 遺伝統計解析 / 原因遺伝子同定 / 染色体異常 / 網羅的遺伝子検査 |
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| Outline of Final Research Achievements |
I developed novel statistical genetics methods to identify variants located in segments of identity-by-decent and chromosomal deletions by using Hamming Distance Ratio (HDR). By applying those methods, I succeeded in identifying genetic variants in 46 mitochondrial cardiomyopathy patients. Among 223 consecutive pediatric mitochondrial disease patients aged <18 years with a confirmed genetic diagnosis including 46 cardiomyopathy patients, The overall survival rate was significantly lower in patients with cardiomyopathy than in those without (p<0.001, log-rank test). By multivariable analysis, left ventricular (LV) hypertrophy (HR=4.6; 95% CI: 2.8-7.3), neonatal onset (HR=2.9; 95% CI: 1.8-4.5) and chromosomal aberrations (HR=2.9; 95% CI: 1.3-6.5) were independent predictors of all-cause mortality. Patients with LV hypertrophy with neonatal onset and/or chromosomal aberrations had higher mortality (100% in 21 patients) than those with LV hypertrophy alone (71% in 14 patients).
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| Academic Significance and Societal Importance of the Research Achievements |
ミトコンドリア心筋症はミトコンドリア病の中でも特に生命予後が悪く、小児例では約80%が主に心不全で死亡する重度の高い疾患である。核遺伝子・ミトコンドリアDNAどちらの遺伝子異常でも生じ、また染色体構造異常によっても発症するため、迅速かつ網羅的な遺伝子診断法の確立が望まれていた。申請者が開発した遺伝統計を用いた新規疾患変異・染色体異常同定ツールを活用し、ミトコンドリア心筋症の診断率向上を達成した。
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