Lin Wei-De, Liao Wen-Ling, Liu Ting-Yuan, Chen Yu-Chia, Liao Chi-Chou, Tsai Fuu-Jen
Department of Medical Research, China Medical University Hospital, No. 2, Yude Road, North District, Taichung City, 404327, Taiwan.
School of Post Baccalaureate Chinese Medicine, China Medical University, Taichung, 404333, Taiwan.
Cell Biosci. 2025 Aug 5;15(1):115. doi: 10.1186/s13578-025-01454-2.
Insulin regulates blood sugar levels and several physiological processes, but many aspects of the relationship between insulin regulation and genes still require further discussion. Thus, this study aimed to explore the genetic variations associated with changes in fasting insulin level in Taiwanese Han individuals through genome-wide association studies (GWAS) and polygenic risk score (PRS) analysis.
Through GWAS in the primary group and replication in the Follow-up group, no genome-wide significant loci were identified; however, three genes or SNPs, PIP4K2A, FTO, and rs3846601, approached significance. Among them, PIP4K2A and rs3846601 represent novel prominent fasting insulin susceptibility loci identified in this study. Consistency was noted among the target, validation, and Follow-up groups by PRS analysis. Significant associations were observed between fasting insulin level-derived PRS and type 2 diabetes (T2D) and BMI susceptibility. Strong and positive associations traits were found between various diseases/traits in PheWAS, they were morbid obesity, T2D, polycystic ovaries, chronic nonalcoholic liver disease, and hypertension.
This study identified fasting insulin-related loci and developed a PRS model, offering insights into genetic regulation and potential early risk assessment for metabolic diseases in Taiwanese Han population.
胰岛素调节血糖水平和多种生理过程，但胰岛素调节与基因之间关系的许多方面仍需进一步探讨。因此，本研究旨在通过全基因组关联研究（GWAS）和多基因风险评分（PRS）分析，探索台湾汉族个体中与空腹胰岛素水平变化相关的基因变异。
通过在原发性组中进行GWAS并在随访组中进行重复验证，未发现全基因组显著位点；然而，三个基因或单核苷酸多态性（SNP），即PIP4K2A、FTO和rs3846601，接近显著水平。其中，PIP4K2A和rs3846601代表了本研究中鉴定出的新的突出的空腹胰岛素易感位点。通过PRS分析在目标组、验证组和随访组之间观察到一致性。观察到空腹胰岛素水平衍生的PRS与2型糖尿病（T2D）和BMI易感性之间存在显著关联。在全基因组关联研究（PheWAS）中发现各种疾病/性状之间存在强正相关性状，它们是病态肥胖、T2D、多囊卵巢、慢性非酒精性肝病和高血压。
本研究鉴定了空腹胰岛素相关位点并建立了PRS模型，为台湾汉族人群代谢疾病的遗传调控和潜在早期风险评估提供了见解。
