Genetic Determinants of the Familial Hypercholesterolaemia Phenotype

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.