Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, London, UK.
Division of Biomedical Sciences, Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UK.
Nat Commun. 2021 May 10;12(1):2579. doi: 10.1038/s41467-021-22338-2.
Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.
血清肝酶浓度与肝功能障碍、代谢和心血管疾病有关。我们利用英国生物库 437438 名参与者的血清丙氨酸转氨酶（ALT）、碱性磷酸酶（ALP）和γ-谷氨酰转移酶（GGT）水平的数据进行了基因分析。在来自百万退伍军人计划、鹿特丹研究和生命线研究的 315572 名欧洲血统个体中进行了复制，证实了 517 个肝酶 SNP。使用鉴定出的 SNP 进行遗传风险评分分析与两个独立的欧洲血统研究（Airwave 健康监测研究和 1966 年芬兰北部出生队列）中的血清肝酶活性强烈相关。使用鉴定出的 SNP 进行基因集富集分析突出了肝脏发育和功能、脂质代谢、胰岛素抵抗和血管形成的参与。孟德尔随机分析表明肝酶变体与冠心病和缺血性中风有关。血清肝酶活性升高的遗传风险评分与体脂百分比、躯干和肝脏以及体重指数较高有关。我们的研究强调了受肝脏调节的分子途径在代谢紊乱和心血管疾病中的作用。
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