Genetic Architecture of Familial Hypercholesterolaemia

Curr Cardiol Rep. 2017 May;19(5):44. doi: 10.1007/s11886-017-0848-8.


Purpose of review: Familial hypercholesterolaemia (FH) is an inherited disorder of low-density lipoprotein cholesterol (LDL-C) which is characterised by a raised cholesterol level from birth and a high risk of premature coronary heart disease. In this paper, we review the genetic basis of FH and its impact on the clinical presentation.

Recent findings: Mutations in any of three genes (LDLR, APOB and PCSK9) are known to cause autosomal dominant FH, but a mutation can be found in only ∼40% of patients with a clinical diagnosis of FH. In the remainder, a polygenic aetiology is most likely, due to the co-inheritance of common LDL-C-raising variants. The cardiovascular presentation and management of FH will differ between patients based on their underlying genetic factors. New genotyping methods such as next-generation sequencing will provide us with better understanding of the genetic architecture of FH.

Keywords: APOB gene; Familial hypercholesterolaemia; LDLR gene; PCSK9 gene; Polygenic hypercholesterolaemia.

Publication types

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

MeSH terms

  • Apolipoprotein B-100 / blood
  • Apolipoprotein B-100 / genetics
  • Cholesterol, LDL / genetics
  • Genome-Wide Association Study
  • Humans
  • Hyperlipoproteinemia Type II / blood
  • Hyperlipoproteinemia Type II / genetics*
  • Multifactorial Inheritance / genetics
  • Mutation / genetics
  • Proprotein Convertase 9 / blood
  • Proprotein Convertase 9 / genetics
  • Receptors, LDL / blood
  • Receptors, LDL / genetics


  • APOB protein, human
  • Apolipoprotein B-100
  • Cholesterol, LDL
  • Receptors, LDL
  • PCSK9 protein, human
  • Proprotein Convertase 9