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Review
. 2023 Feb;293(2):144-165.
doi: 10.1111/joim.13577. Epub 2022 Oct 17.

Genetic and molecular architecture of familial hypercholesterolemia

Marianne Abifadel  1   2 , Catherine Boileau  1   3
Affiliations
Review

Genetic and molecular architecture of familial hypercholesterolemia

Marianne Abifadel et al. J Intern Med. 2023 Feb.

Abstract

Atherosclerotic cardiovascular disease is the leading cause of death globally. Despite its important risk of premature atherosclerosis and cardiovascular disease, familial hypercholesterolemia (FH) is still largely underdiagnosed worldwide. It is one of the most frequently inherited diseases due to mutations, for autosomal dominant forms, in either of the LDLR, APOB, and PCSK9 genes or possibly a few mutations in the APOE gene and, for the rare autosomal forms, in the LDLRAP1 gene. The discovery of the genes implicated in the disease has largely helped to improve the diagnosis and treatment of FH from the LDLR by Brown and Goldstein, as well as the introduction of statins, to PCSK9 discovery in FH by Abifadel et al., and the very rapid availability of PCSK9 inhibitors. In the last two decades, major progress has been made in clinical and genetic diagnostic tools and the therapeutic arsenal against FH. Improving prevention, diagnosis, and treatment and making them more accessible to all patients will help reduce the lifelong burden of the disease.

Keywords: APOB; APOE; LDLR; PCSK9; familial hypercholesterolemia; gene; mutation; polygenic.

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Conflict of interest statement

No conflict of interest was declared.

Figures

Fig. 1
Fig. 1
Key steps of familial hypercholesterolemia timeline.
Fig. 2
Fig. 2
Genetic architecture and genes associated with familial hypercholesterolemia (FH). The various genetic architectures (mono, oligo, and polygenic) are defined with respect to the frequency of the alleles (specific DNA sequence) involved and the effect of the DNA variants they carry on the biological function of the encoded protein. Genes carrying pathogenic variants in autosomal dominant FH are shown in red; genes carrying pathogenic variants in autosomal recessive FH are in blue. The genes carrying variants implicated in polygenic FH are all in purple or green for those studied in polygenic risk score calculations.
Fig. 3
Fig. 3
PCSK9 timeline—from discovery to targeted therapies.
Fig. 4
Fig. 4
Cellular localization of the various protagonists encoded by the genes mutated in familial hypercholesterolemia.
See this image and copyright information in PMC

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