{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T07:48:42Z","timestamp":1790668122199,"version":"4.1.0"},"reference-count":55,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 &gt; 5.0 mmol\/L and available NGS data. We analyzed rare variants in LPL, APOC2, APOA5, GPIHBP1, LMF1, and APOE; the \u03b52\/\u03b52 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 \u03b52\/\u03b52 genotype (18.7%, overlapping with chylomicronemia variants in 4.1%), and an extreme polygenic burden (35.8%; PRS &gt; 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\u201324-fold higher odds of pancreatitis compared with other groups (p &lt; 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 &lt; 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.<\/jats:p>","DOI":"10.3390\/ijms27125443","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T03:27:21Z","timestamp":1781666841000},"page":"5443","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Genetic Determinants of Severe Hypertriglyceridemia: Rare Variants in LPL, APOC2, APOA5, GPIHBP1, LMF1, APOE and Polygenic Risk"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3019-3961","authenticated-orcid":false,"given":"Anastasia V.","family":"Blokhina","sequence":"first","affiliation":[{"name":"National Medical Research Center for Therapy and Preventive Medicine, Ministry of Healthcare of the Russian Federation, Petroverigsky per. 10, Bld. 3, 101000 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5989-6233","authenticated-orcid":false,"given":"Alexey N.","family":"Meshkov","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Therapy and Preventive Medicine, Ministry of Healthcare of the Russian Federation, Petroverigsky per. 10, Bld. 3, 101000 Moscow, Russia"},{"name":"Department of General and Medical Genetics, Pirogov Russian National Research Medical University, 1, Ostrovityanova Str., 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra I.","family":"Ershova","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Therapy and Preventive Medicine, Ministry of Healthcare of the Russian Federation, Petroverigsky per. 10, Bld. 3, 101000 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2798-9811","authenticated-orcid":false,"given":"Marija","family":"Zaicenoka","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Therapy and Preventive Medicine, Ministry of Healthcare of the Russian Federation, Petroverigsky per. 10, Bld. 3, 101000 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5375-7328","authenticated-orcid":false,"given":"Viktoria I.","family":"Mikhailina","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Therapy and Preventive Medicine, Ministry of Healthcare of the Russian Federation, Petroverigsky per. 10, Bld. 3, 101000 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8493-4761","authenticated-orcid":false,"given":"Stepan A.","family":"Smetnev","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Therapy and Preventive Medicine, Ministry of Healthcare of the Russian Federation, Petroverigsky per. 10, Bld. 3, 101000 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5932-1744","authenticated-orcid":false,"given":"Anna A.","family":"Bukaeva","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Therapy and Preventive Medicine, Ministry of Healthcare of the Russian Federation, Petroverigsky per. 10, Bld. 3, 101000 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1500-3696","authenticated-orcid":false,"given":"Alena. S.","family":"Limonova","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Therapy and Preventive Medicine, Ministry of Healthcare of the Russian Federation, Petroverigsky per. 10, Bld. 3, 101000 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4765-8021","authenticated-orcid":false,"given":"Anna V.","family":"Kiseleva","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Therapy and Preventive Medicine, Ministry of Healthcare of the Russian Federation, Petroverigsky per. 10, Bld. 3, 101000 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evgeniia A.","family":"Sotnikova","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Therapy and Preventive Medicine, Ministry of Healthcare of the Russian Federation, Petroverigsky per. 10, Bld. 3, 101000 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0723-0493","authenticated-orcid":false,"given":"Anastasia A.","family":"Zharikova","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Therapy and Preventive Medicine, Ministry of Healthcare of the Russian Federation, Petroverigsky per. 10, Bld. 3, 101000 Moscow, Russia"},{"name":"Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 1-73, Leninskie Gory, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9354-3383","authenticated-orcid":false,"given":"Elizaveta A.","family":"Novokhatskaya","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Therapy and Preventive Medicine, Ministry of Healthcare of the Russian Federation, Petroverigsky per. 10, Bld. 3, 101000 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9135-1794","authenticated-orcid":false,"given":"Elizaveta V.","family":"Baranovskaya","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Therapy and Preventive Medicine, Ministry of Healthcare of the Russian Federation, Petroverigsky per. 10, Bld. 3, 101000 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri V.","family":"Vyatkin","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Therapy and Preventive Medicine, Ministry of Healthcare of the Russian Federation, Petroverigsky per. 10, Bld. 3, 101000 Moscow, Russia"},{"name":"Department of Natural Sciences, Novosibirsk State University, 1, Pirogova Str., 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7867-9509","authenticated-orcid":false,"given":"Vasily E.","family":"Ramensky","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Therapy and Preventive Medicine, Ministry of Healthcare of the Russian Federation, Petroverigsky per. 10, Bld. 3, 101000 Moscow, Russia"},{"name":"Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 1-73, Leninskie Gory, 119991 Moscow, Russia"},{"name":"Institute for Artificial Intelligence, Lomonosov Moscow State University, 1-73, Leninskie Gory, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria S.","family":"Pokrovskaya","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Therapy and Preventive Medicine, Ministry of Healthcare of the Russian Federation, Petroverigsky per. 10, Bld. 3, 101000 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0323-2635","authenticated-orcid":false,"given":"Oxana M.","family":"Drapkina","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Therapy and Preventive Medicine, Ministry of Healthcare of the Russian Federation, Petroverigsky per. 10, Bld. 3, 101000 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1093\/eurheartj\/ehz455","article-title":"2019 ESC\/EAS Guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS)","volume":"41","author":"Mach","year":"2020","journal-title":"Eur. 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