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Genetic Determinants of the Familial Hypercholesterolaemia Phenotype

Humphries, Steve Eric; Futema, Marta; (2025) Genetic Determinants of the Familial Hypercholesterolaemia Phenotype. Annals of Human Genetics , 89 (5) pp. 293-304. 10.1111/ahg.12594. Green open access

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Abstract

Individuals with familial hypercholesterolaemia (FH) have severely elevated plasma concentrations of low-density lipoprotein cholesterol (LDL-C) from birth and as a consequence have an elevated morbidity and mortality due to the development of coronary heart disease (CHD). Monogenic FH can be caused by carrying a single copy of a pathogenic variant in any of four genes (LDLR/APOB/PCSK9/APOE), which are all involved in the clearance of LDL-C from the blood by the liver. FH is one of the most common inherited disorders, with an estimated prevalence of carriers of around 1/280 individuals in most populations and ancestry groups. However, such variants can be found usually only in 20%–30% of clinically FH subjects, and in the majority of the no-variant individuals, the phenotype is most likely explained by the inheritance of a greater-than-average number of common variants of small effect, with such individuals better given the diagnosis of ‘polygenic hypercholesterolaemia’. Also, in a proportion of no-variant subjects who meet the clinical criteria, the most likely explanation is due to overproduction of Lp(a) which is an LDL-C particle with a bound copy of the ‘little-a’ protein. Here, we review the research that has elucidated the genetic architecture of the FH phenotype and discuss recent studies and future prospects of finding additional genes where variants can cause FH.

Type: Article
Title: Genetic Determinants of the Familial Hypercholesterolaemia Phenotype
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/ahg.12594
Publisher version: https://doi.org/10.1111/ahg.12594
Language: English
Additional information: Copyright © 2025 The Author(s). Annals of Human Genetics published by University College London (UCL) and John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. This is an open access article under the terms of the Creative Commons Attribution License, https://creativecommons.org/licenses/by/4.0/, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
URI: https://discovery.ucl.ac.uk/id/eprint/10212629
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