Fan Hsien-Yu, Tsai Ming-Chieh, Lai Chih-Jun, Yeh Chiu-Li, Hsu Hsin-Yin, Lai Po-Jui, Hsu Hsiu-Ching, Su Ta-Chen, Lin Hung-Ju, Lin Yen-Feng, Lu Tzu-Pin, Chien Kuo-Liong
School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University.
Institute of Epidemiology and Preventive Medicine, National Taiwan University.
Circ J. 2025 Feb 25;89(3):331-339. doi: 10.1253/circj.CJ-24-0491. Epub 2024 Dec 11.
There are limited data on the use of whole-exome sequencing (WES) to diagnose severe hypertriglyceridemia. Our aim was to identify candidate genes linked to triglyceride levels via a genome-wide association study (GWAS) and to recruit participants with severe hypertriglyceridemia for WES to assess allelic variants in the candidate genes.
A GWAS was conducted involving 120,140 participants to identify lead loci associated with blood triglyceride levels. Following the identification of these lead loci, WES was performed on DNA samples from 29 participants with hypertriglyceridemia whose triglyceride levels exceeded 800 mg/dL to assess variations in the corresponding genes. In the GWAS of 120,140 participants, the apolipoprotein A5 (APOA5) locus on chromosome 11 showed the strongest association with blood triglyceride levels (lead single nucleotide polymorphism [SNP] rs2075291; P=3.07×10), along with 5 independent SNPs (most significant P=7.84×10). Other key loci included BUD13 homolog (BUD13; P=2.73×10), glucokinase regulator (GCKR; P=2.63×10), and lipoprotein lipase (LPL; P=1.50×10). WES in 29 hypertriglyceridemia patients identified additional genes, including ALDH1A2, APOC1, LPL, RGS7, and SIK3, showing significant allele frequency variations and potential roles in lipid metabolism.
Our study confirms the role of known genetic loci in triglyceride metabolism and hypertriglyceridemia while uncovering novel loci, offering new perspectives on lipid regulation and potential avenues for therapeutic advancements.
关于使用全外显子组测序（WES）诊断严重高甘油三酯血症的数据有限。我们的目的是通过全基因组关联研究（GWAS）确定与甘油三酯水平相关的候选基因，并招募患有严重高甘油三酯血症的参与者进行WES，以评估候选基因中的等位基因变异。
对120140名参与者进行了GWAS，以确定与血液甘油三酯水平相关的主要位点。在确定这些主要位点后，对29名甘油三酯水平超过800mg/dL的高甘油三酯血症参与者的DNA样本进行了WES，以评估相应基因的变异情况。在对120140名参与者的GWAS中，11号染色体上的载脂蛋白A5（APOA5）位点与血液甘油三酯水平显示出最强的关联（主要单核苷酸多态性[SNP]rs2075291；P=3.07×10），还有5个独立的SNP（最显著的P=7.84×10）。其他关键位点包括BUD13同源物（BUD13；P=2.73×10）、葡萄糖激酶调节蛋白（GCKR；P=2.63×10）和脂蛋白脂肪酶（LPL；P=1.50×10）。对29名高甘油三酯血症患者进行的WES鉴定出了其他基因，包括ALDH1A2、APOC1、LPL、RGS7和SIK3，这些基因显示出显著的等位基因频率变异以及在脂质代谢中的潜在作用。
我们的研究证实了已知基因位点在甘油三酯代谢和高甘油三酯血症中的作用，同时发现了新的位点，为脂质调节提供了新的视角以及治疗进展的潜在途径。
