Genetic and molecular architecture of familial hypercholesterolemia

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


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.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atherosclerosis* / genetics
  • Cardiovascular Diseases*
  • Humans
  • Hyperlipoproteinemia Type II* / diagnosis
  • Hyperlipoproteinemia Type II* / genetics
  • Hyperlipoproteinemia Type II* / therapy
  • Mutation
  • Phenotype
  • Proprotein Convertase 9 / genetics
  • Receptors, LDL / genetics


  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Receptors, LDL