Genetic Determinants of Severe Hypertriglyceridemia: Rare Variants in LPL, APOC2, APOA5, GPIHBP1, LMF1, APOE and Polygenic Risk.

Severe hypertriglyceridemia (HTG) is genetically heterogeneous, but its genetic architecture remains incompletely characterized. We investigated the genetic determinants of severe HTG in 123 patients with triglyceride (TG) levels > 5.0 mmol/L and available NGS data. We analyzed rare variants in LPL, APOC2, APOA5, GPIHBP1, LMF1, and APOE; the ε2/ε2 APOE genotype; and TG-polygenic risk score (PRS) based on 40 variants. Major genetic determinants were identified in 65.0% of individuals, including rare variants in chylomicronemia genes (24.4%; 28 variants, including 10 novel, 53.6% in LPL), rare APOE variants or the ε2/ε2 genotype (18.7%, overlapping with chylomicronemia variants in 4.1%), and an extreme polygenic burden (35.8%; PRS > 90th percentile), including 26.0% with isolated polygenic HTG. The remaining 35.0% had moderate-to-low PRS. The cohort was categorized into familial chylomicronemia syndrome (FCS, n = 7), multifactorial chylomicronemia syndrome (MCS, n = 21), polygenic HTG (n = 32), familial dysbetalipoproteinemia (FD, n = 20), and moderate-to-low PRS (n = 43) groups based on genetic determinants. FCS had the lowest PRS percentile (median 26) and the most distinct clinical profile, with the highest TG levels (median 30.60 mmol/L) and 6-24-fold higher odds of pancreatitis compared with other groups (p < 0.05), alongside a lower body mass index (median 23.0 kg/m2) than all groups except MCS, whereas FD had the lowest TG levels (10.20 mmol/L, p < 0.05). These results further advance the understanding of the complex genetic architecture of severe HTG and demonstrate that broader genetic analysis, including APOE and TG-PRS, may increase the yield of genetic determinants in severe HTG.