2020 Fiscal Year Final Research Report

Joint International Research for identification of disease-susceptible genes and drug-sensitive genes in childhood nephrotic syndrome

Research Project

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Project/Area Number	18KK0244
Research Category	Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))
Allocation Type	Multi-year Fund
Review Section	Medium-sized Section 53:Organ-based internal medicine and related fields
Research Institution	Kobe University
Principal Investigator	IIJIMA KAZUMOTO 神戸大学, 医学研究科, 教授 (00240854)
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)
Project Period (FY)	2018-10-09 – 2021-03-31
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
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).
Free Research Field	腎臓学
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。