Lin Eugene, Yan Yu-Ting, Chen Mu-Hong, Yang Albert C, Kuo Po-Hsiu, Tsai Shih-Jen
Department of Genome Sciences, University of Washington, Seattle, WA, USA.
Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, ROC.
Nat Commun. 2025 Apr 14;16(1):3525. doi: 10.1038/s41467-025-58506-x.
This pioneering genome-wide association study examined surrogate markers for insulin resistance (IR) in 147,880 Taiwanese individuals using data from the Taiwan Biobank. The study focused on two IR surrogate markers: the triglyceride to high-density lipoprotein cholesterol (TG:HDL-C) ratio and the TyG index (the product of fasting plasma glucose and triglycerides). We identified genome-wide significance loci within four gene clusters: GCKR, MLXIPL, APOA5, and APOC1, uncovering 197 genes associated with IR. Transcriptome-wide association analysis revealed significant associations between these clusters and TyG, primarily in adipose tissue. Gene ontology analysis highlighted pathways related to Alzheimer's disease, glucose homeostasis, insulin resistance, and lipoprotein dynamics. The study identified sex-specific genes associated with TyG. Polygenic risk score analysis linked both IR markers to gout and hyperlipidemia. Our findings elucidate the complex relationships between IR surrogate markers, genetic predisposition, and disease phenotypes in the Taiwanese population, contributing valuable insights to the field of metabolic research.
这项开创性的全基因组关联研究利用台湾生物银行的数据，对147,880名台湾个体的胰岛素抵抗（IR）替代标志物进行了检测。该研究聚焦于两种IR替代标志物：甘油三酯与高密度脂蛋白胆固醇（TG:HDL-C）的比值以及TyG指数（空腹血糖与甘油三酯的乘积）。我们在四个基因簇（GCKR、MLXIPL、APOA5和APOC1）中确定了全基因组显著位点，发现了197个与IR相关的基因。全转录组关联分析揭示了这些基因簇与TyG之间的显著关联，主要存在于脂肪组织中。基因本体分析突出了与阿尔茨海默病、葡萄糖稳态、胰岛素抵抗和脂蛋白动态相关的途径。该研究确定了与TyG相关的性别特异性基因。多基因风险评分分析将两种IR标志物与痛风和高脂血症联系起来。我们的研究结果阐明了台湾人群中IR替代标志物、遗传易感性和疾病表型之间的复杂关系，为代谢研究领域提供了有价值的见解。
