| Project/Area Number |
17K09864
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Jichi Medical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
渡邉 和寿 自治医科大学, 医学部, 講師 (60724416)
宮下 洋 自治医科大学, 医学部, 教授 (90301449)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 非アルコール性脂肪肝 / ゲノムワイド関連解析 / 腸内細菌叢 / マウスモデル / メタボリック症候群 / ゲノムコホート / メタゲノム |
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| Outline of Final Research Achievements |
Non-alcoholic fatty liver disease (NAFLD) is supposed to manifest its metabolic phenotype in the liver, but it is common to have lean individuals who are diagnosed with NAFLD. metabolically healthy normal-weight NAFLD patients (n=275) were compared with non-NAFLD controls (n=1,411) adjusted for age, sex, and alcohol consumption by a genome-wide association study (GWAS). HLA in chr6, MIR548F3 in chr7, MYL2 in chr12 and GPC6 in chr13 were suggested by the GWAS, which were further assessed by SNP association analysis of whole NAFLD against non-NAFLD in 9,726 members of the general population. The lead SNP in chr6 was significantly replicated with increased NAFLD risk. Imputation based and next generation sequence-based typing of HLA showed the significant increase of the HLA-B*54:01 allele. Fecal metagenomic analysis of 3,420 members of the general population showed significant dissimilarity in beta-diversity analysis of HLA-B*54:01 allele carriers.
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| Academic Significance and Societal Importance of the Research Achievements |
糖尿病や肥満などを合併しない脂肪肝の遺伝的背景を調べることによって、新たな関連する遺伝子座、HLAを発見した。どのようにHLAが脂肪肝の易罹患性に関わるかについて、脂肪肝との深い関連が観察されている腸内細菌叢を調べた結果、脂肪肝のリスクを高めるHLAタイプを持つ人は脂肪肝を発症しやすい特徴を持つことが明らかになった。メタボリック症候群の増加に伴って脂肪肝の有病率も高まっており、病状が進行すれば肝硬変から肝癌の原因にもなる脂肪肝炎は将来、ウイルス性肝炎を凌駕する肝疾患となることが危惧されている。今回の発見によって、脂肪肝の予防や治療に新たな戦略を生み出すきっかけになることが期待される。
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