{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T13:27:03Z","timestamp":1783517223660,"version":"3.55.0"},"reference-count":154,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T00:00:00Z","timestamp":1782000000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>High levels of low-density lipoprotein cholesterol (LDL-c) have been recognized as the main causal factor of atherosclerotic cardiovascular disease (ASCVD) and are influenced by both genetic and environmental factors. Among genetic determinants, Familial Hypercholesterolemia (FH) is the most common monogenic disorder, caused by rare high-impact variants in genes involved in LDL uptake. Other monogenic causes of hypercholesterolemia include sitosterolemia, cerebrotendinous xanthomatosis and lysosomal acid lipase deficiency (LALD). However, monogenic disorders only account for a small proportion of inherited hypercholesterolemia. In many individuals, increased LDL-c levels are caused by the contemporary presence of different single-nucleotide polymorphisms (SNPs) with a moderate\/low impact. These SNPs could be summarized through polygenic risk scores (PRS) that attribute relative weight to each of these. Another genetic determinant of hypercholesterolemic phenotypes is high levels of lipoprotein(a)\u2014Lp(a). Lp(a) is an LDL particle modified by the binding of apolipoprotein(a)\u2014apo(a)\u2014which represents an independent risk factor for ASCVD. Lp(a) levels are mainly genetically determined by variation in the number of kringle IV type 2 (K-IV2) repeats, as well as by several SNPs, and remain stable throughout life. The aim of this narrative review is to report an updated overview of the genetic mechanisms underlying hypercholesterolemia, including monogenic disorders, PRS and Lp(a), focusing on their potential repercussion in clinical practice by the integration into cardiovascular risk stratification beyond traditional clinical assessment. This integration could lead to a more comprehensive and individualized approach to cardiovascular prevention, with emerging perspectives including the possible use of artificial intelligence (AI).<\/jats:p>","DOI":"10.3390\/genes17060721","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T14:27:52Z","timestamp":1783434472000},"page":"721","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Influence on LDL-Cholesterol Levels: Role of Polygenic Risk Scores and Lp(a) Beyond Monogenic Hypercholesterolemia"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-7566-7314","authenticated-orcid":false,"given":"Martina","family":"Ferrandino","sequence":"first","affiliation":[{"name":"Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 Degli Studi di Napoli Federico II, Via Pansini 5, 80131 Naples, Italy"},{"name":"CEINGE Biotecnologie Avanzate Franco Salvatore, Via Gaetano Salvatore 486, 80145 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ylenia","family":"Cerrato","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 Degli Studi di Napoli Federico II, Via Pansini 5, 80131 Naples, Italy"},{"name":"CEINGE Biotecnologie Avanzate Franco Salvatore, Via Gaetano Salvatore 486, 80145 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7392-5544","authenticated-orcid":false,"given":"Gabriella","family":"Iannuzzo","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Clinica e Chirurgia, Universit\u00e0 Degli Studi di Napoli Federico II, Via Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8077-2809","authenticated-orcid":false,"given":"Ilenia Lorenza","family":"Calcaterra","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Clinica e Chirurgia, Universit\u00e0 Degli Studi di Napoli Federico II, Via Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8059-3819","authenticated-orcid":false,"given":"Matteo Nicola Dario","family":"Di Minno","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Clinica e Chirurgia, Universit\u00e0 Degli Studi di Napoli Federico II, Via Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliana","family":"Fortunato","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 Degli Studi di Napoli Federico II, Via Pansini 5, 80131 Naples, Italy"},{"name":"CEINGE Biotecnologie Avanzate Franco Salvatore, Via Gaetano Salvatore 486, 80145 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0618-7940","authenticated-orcid":false,"given":"Maria Donata","family":"Di Taranto","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 Degli Studi di Napoli Federico II, Via Pansini 5, 80131 Naples, Italy"},{"name":"CEINGE Biotecnologie Avanzate Franco Salvatore, Via Gaetano Salvatore 486, 80145 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,21]]},"reference":[{"key":"ref_1","first-page":"1200","article-title":"LDL Cholesterol Management Simplified in Adults-Lower for Longer Is Better: Guidance from the National Lipid Association","volume":"19","author":"Jackson","year":"2025","journal-title":"J. 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