Genetic Variants in Severe Hypertriglyceridemia Among Taiwanese Participants　- Insights From Genome-Wide Association and Whole-Exome Sequencing Analyses

BACKGROUND: 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. METHODS AND RESULTS: 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=3.07×10-108), along with 5 independent SNPs (most significant P=7.84×10-167). Other key loci included BUD13 homolog (BUD13; P=2.73×10-62), glucokinase regulator (GCKR; P=2.63×10-24), and lipoprotein lipase (LPL; P=1.50×10-11). 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. CONCLUSIONS: 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.