Genetic Architecture of Familial Hypercholesterolaemia

Abstract

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.

Fig. 1

Monogenic and polygenic causes of elevated plasma total cholesterol. Mutations that cause loss of function in LDLR or APOB or gain of function in PCSK9 result in an individual moving from a low point in the population cholesterol distribution to being over the diagnostic cut-off for familial hypercholesterolaemia (7.5 mmol/l). Mutations in PCSK9 are the most severe and in APOB, the mildest. The possibility that mutations in STAP1 may cause FH is shown. These individuals have ‘monogenic FH.’ It is also possible to have total cholesterol levels above the FH diagnostic cut-off by having inherited a greater than average number of common cholesterol-raising variants (SNP2, SNP2 etc) each of modest effect. As shown in (5), key SNPs are in LDLR, APOB, APOE (2×) ABCG8 and SORT1. These individuals have a ‘polygenic’ cause of their hypercholesterolaemia. In more than 80% of those with a clinical diagnosis of FH but with no detectable mutation in LDLR/APOB/PCSK9, the polygenic explanation is most likely. In the remainder, mutation in a novel gene may be present