Genetics
Polygenic risk scores and Lp(a) extend genetic risk stratification beyond monogenic hypercholesterolaemia, review (Genes Basel 2026)
Original title: Genetic Influence on LDL-Cholesterol Levels: Role of Polygenic Risk Scores and Lp(a) Beyond Monogenic Hypercholesterolemia
Narrative review of the genetic determinants of LDL-cholesterol, spanning monogenic disorders (familial hypercholesterolaemia, sitosterolaemia, cerebrotendinous xanthomatosis, lysosomal acid lipase deficiency), polygenic risk scores that aggregate many low-impact SNPs, and Lp(a), an LDL-like particle whose level is mainly determined by kringle IV type 2 repeat number and additional SNPs and remains stable throughout life. The authors argue monogenic disorders explain only a small share of inherited hypercholesterolaemia, and that integrating polygenic risk scores and Lp(a) into cardiovascular risk stratification, potentially aided by artificial intelligence, could give a more comprehensive and individualised approach to prevention than traditional clinical assessment alone.
Original abstract
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)-Lp(a). Lp(a) is an LDL particle modified by the binding of apolipoprotein(a)-apo(a)-which 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).
familial hypercholesterolaemiageneticsrisk prediction
Summary written by lp-a.org from the published abstract; figures as published. Page updated 17 August 2026. Methods.