Genetic Determinants of Severe Hypertriglyceridemia: Rare Variants in LPL, APOC2, APOA5, GPIHBP1, LMF1, APOE and Polygenic Risk.
AV, B., AN, M., AI, E., M, Z., VI, M., SA, S., AA, B., AS, L., AV, K., & EA, S. (2026). Genetic Determinants of Severe Hypertriglyceridemia: Rare Variants in LPL, APOC2, APOA5, GPIHBP1, LMF1, APOE and Polygenic Risk.. International journal of molecular sciences. https://doi.org/10.3390/ijms27125443
AV B, AN M, AI E, M Z, VI M, SA S, et al. Genetic Determinants of Severe Hypertriglyceridemia: Rare Variants in LPL, APOC2, APOA5, GPIHBP1, LMF1, APOE and Polygenic Risk.. International journal of molecular sciences. 2026; doi: 10.3390/ijms27125443
AV B, AN M, AI E, et al. Genetic Determinants of Severe Hypertriglyceridemia: Rare Variants in LPL, APOC2, APOA5, GPIHBP1, LMF1, APOE and Polygenic Risk.[J]. International journal of molecular sciences. 2026. DOI: 10.3390/ijms27125443.
@article{av2026,
author = {Blokhina AV and Meshkov AN and Ershova AI and Zaicenoka M and Mikhailina VI and Smetnev SA and Bukaeva AA and Limonova AS and Kiseleva AV and Sotnikova EA},
title = {Genetic Determinants of Severe Hypertriglyceridemia: Rare Variants in LPL, APOC2, APOA5, GPIHBP1, LMF1, APOE and Polygenic Risk.},
journal = {International journal of molecular sciences},
year = {2026},
doi = {10.3390/ijms27125443},
note = {PMID: 42353159},
}
TY - JOUR AU - Blokhina AV AU - Meshkov AN AU - Ershova AI AU - Zaicenoka M AU - Mikhailina VI AU - Smetnev SA AU - Bukaeva AA AU - Limonova AS AU - Kiseleva AV AU - Sotnikova EA TI - Genetic Determinants of Severe Hypertriglyceridemia: Rare Variants in LPL, APOC2, APOA5, GPIHBP1, LMF1, APOE and Polygenic Risk. T2 - International journal of molecular sciences PY - 2026 DO - 10.3390/ijms27125443 AN - PMID:42353159 ER -
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.