Understanding Pathways of Liver Injury Pathogenesis by Genome and Metabolome Cohort and its Application to Personalized Preventive Medicine

Research Project

Project/Area Number	18KT0074
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	特設分野
Research Field	Complex Systems Disease Theory
Research Institution	Keio University
Principal Investigator	Harada Sei 慶應義塾大学, 医学部(信濃町), 講師 (10738090)
Co-Investigator(Kenkyū-buntansha)	中杤昌弘名古屋大学, 医学系研究科(保健), 准教授 (10559983) 竹内文乃慶應義塾大学, 医学部(信濃町), 講師 (80511196)
Project Period (FY)	2018-07-18 – 2023-03-31
Project Status	Completed (Fiscal Year 2022)
Budget Amount *help	¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000) Fiscal Year 2020: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000) Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000) Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywords	分子疫学 / 個別的予防医療 / メタボローム / ゲノム / コホート研究 / 肝障害 / メタボローム疫学 / ゲノム疫学 / アルコール / 遺伝-環境交互作用 / メタボロミクス疫学 / GWAS / 前向きコホート研究
Outline of Final Research Achievements	In this study, using genomic and metabolomic data of 1000 subjects whose plasma metabolome was measured repeatedly every 3 years and 3-year follow-up data of lifestyle and health checkups, we constructed a model to predict the development of alcoholic/non-alcoholic liver injury and to clarify the causal relationship between genetic and environmental factors and their interaction with liver injury in terms of The objective of this study was to clarify the causal relationship between genetic and environmental factors and their interactions and liver injury by pathway from the viewpoint of metabolic mechanisms. We conducted metabolomic analysis using multiple measurement systems and pathway analysis and mediation analysis to evaluate genome-lifestyle-metabolism-liver injury in an integrated manner, and constructed a model for alcoholic/non-alcoholic liver injury through metabolic variation due to the interaction of genetic and environmental factors.
Academic Significance and Societal Importance of the Research Achievements	ゲノム研究の進展により、疾病の遺伝的要因の解明が進む一方、多因子疾患の発症要因は複雑で、遺伝-環境交互作用を含めたメカニズムの解明や、個別的発症予測モデルの構築は道半ばである。この進展のためには、前向きコホートでの遺伝・環境要因の収集に加え、体内の代謝動態を網羅的に測定するメタボローム解析を導入し、多因子の体内への複合影響を評価する手法が有用と考えた。本研究では、アルコール性/非アルコール性肝障害をモデルケースとして、遺伝要因と環境要因の交互作用により、代謝変動を通じて肝障害の発症に至るモデルの構築を行い、ゲノム-メタボロームコホートの個別的予防医療における有用性を示した。