美国密歇根大学医学院Elizabeth K. Speliotes团队，进行了英国生物库中胰岛素抵抗(IR)标志物甘油三酯与高密度脂蛋白胆固醇(TG:HDL-C)的综合遗传学研究。相关论文于2024年1月10日发表在《自然—遗传学》杂志上。

他们对英国生物银行402398名欧洲人的TG:HDL-C比率进行了全基因组关联研究。他们鉴定出369个独立的SNP，其中114个在其他IR全基因组研究中具有假发现率调整后的P值< 0.05，使其成为高可信度IR相关位点。这114个基因座中有72个以前没有与IR相关。经全现象分析，这114个基因座可分为5组，富含胰岛素信号传导、脂肪细胞生理和蛋白质代谢的重要候选基因。

他们使用密歇根基因组计划中的51,550名欧洲人，从高置信度IR相关位点创建了多基因风险评分。他们确定了与糖尿病、高甘油血症、高血压、非酒精性脂肪性肝病和缺血性心脏病的关联。总的来说，这项研究提供了对IR关键的基因、途径、组织和亚型的深入了解。

据介绍，IR是公认的代谢性疾病的危险因素。TG:HDL-C的比值是IR的替代标志物。

附：英文原文

Title: Comprehensive genetic study of the insulin resistance marker TG:HDL-C in the UK Biobank

Author: Oliveri, Antonino, Rebernick, Ryan J, Kuppa, Annapurna, Pant, Asmita, Chen, Yanhua, Du, Xiaomeng, Cushing, Kelly C., Bell, Hannah N, Raut, Chinmay, Prabhu, Ponnandy, Chen, Vincent L., Halligan, Brian D., Speliotes, Elizabeth K.

Issue&Volume: 2024-01-10

Abstract: Insulin resistance (IR) is a well-established risk factor for metabolic disease. The ratio of triglycerides to high-density lipoprotein cholesterol (TG:HDL-C) is a surrogate marker of IR. We conducted a genome-wide association study of the TG:HDL-C ratio in 402,398 Europeans within the UK Biobank. We identified 369 independent SNPs, of which 114 had a false discovery rate-adjusted P value<0.05 in other genome-wide studies of IR making them high-confidence IR-associated loci. Seventy-two of these 114 loci have not been previously associated with IR. These 114 loci cluster into five groups upon phenome-wide analysis and are enriched for candidate genes important in insulin signaling, adipocyte physiology and protein metabolism. We created a polygenic-risk score from the high-confidence IR-associated loci using 51,550 European individuals in the Michigan Genomics Initiative. We identified associations with diabetes, hyperglyceridemia, hypertension, nonalcoholic fatty liver disease and ischemic heart disease. Collectively, this study provides insight into the genes, pathways, tissues and subtypes critical in IR.

DOI: 10.1038/s41588-023-01625-2

Source: https://www.nature.com/articles/s41588-023-01625-2