| Project/Area Number |
18KK0244
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| Research Category |
Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 53:Organ-based internal medicine and related fields
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| Research Institution | Kobe University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
人見 祐基 星薬科大学, 薬学部, 特任講師 (10525819)
堀之内 智子 神戸大学, 医学研究科, 助教 (30754593)
長野 智那 神戸大学, 医学研究科, 助教 (60814316)
野津 寛大 神戸大学, 医学研究科, 特命教授 (70362796)
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| Project Period (FY) |
2018-10-09 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2020: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2019: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2018: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
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| Keywords | ステロイド感受性ネフローゼ症候群 / ゲノムワイド関連解析 / 疾患感受性遺伝子 / ネフリン / フィンランド型先天性ネフローゼ症候群 / 腎臓学 / 器官システム内科学 |
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| Outline of Final Research Achievements |
To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P=4.94E-20, odds ratio (OR) =1.90) and TNFSF15 (rs6478109, P=2.54E-8, OR=0.72) regions achieved genome-wide significance and were replicated in Korean, South Asian and African populations. Trans-ethnic meta-analyses including Japanese, Korean, South Asian, African, European, Hispanic and Maghrebian populations confirmed the significant associations of variants in NPHS1-KIRREL2 (Pmeta=6.71E-28, OR=1.88) and TNFSF15 (Pmeta=5.40E-11, OR=1.33) loci. Analysis of the NPHS1 risk alleles with glomerular NPHS1 mRNA expression from the same person revealed allele specific expression with significantly lower expression of the transcript derived from the risk haplotype (Wilcox test p=9.3E-4).
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は、希少なメンデル遺伝病であるフィンランド型先天性ネフローゼ症候群の病因遺伝子NPHS1が、小児腎疾患で最も頻度の高い多因子疾患であるステロイド感受性ネフローゼ症候群の疾患感受性遺伝子でもあることを明らかにしたものであり、ステロイド感受性ネフローゼ症候群の発症機序における遺伝学的理解を導くための重要なマイルストーンとなるとともに、腎臓病学におけるパラダイムシフトとなる研究である。
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