The genetic basis of familial hypercholesterolemia: inheritance, linkage, and mutations

Appl Clin Genet. 2010 Aug 5;3:53-64. doi: 10.2147/tacg.s8285. Print 2010.


Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism characterized by high plasma concentrations of low-density lipoprotein cholesterol (LDLc), tendon xanthomas, and increased risk of premature coronary heart disease. FH is one of the most common inherited disorders; there are 10,000,000 people with FH worldwide, mainly heterozygotes. The most common FH cause is mutations along the entire gene that encode for LDL receptor (LDLR) protein, but it has been also described that mutations in apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 genes produce this phenotype. About 17%-33% of patients with a clinical diagnosis of monogenic hypercholesterolemia do not harbor any genetic cause in the known loci. Because FH has been considered as a public health problem, it is very important for an early diagnosis and treatment. Recent studies have demonstrated the influence of the LDLR mutation type in the FH phenotype, associating a more severe clinical phenotype and worse advanced carotid artherosclerosis in patients with null than those with receptor-defective mutations. Since 2004, a molecular FH diagnosis based on a genetic diagnostic platform (Lipochip(®); Progenika-Biopharma, Derio, Spain) has been developed. This analysis completes the adequate clinical diagnosis made by physicians. Our group has recently proposed new FH guidelines with the intention to facilitate the FH diagnosis. The treatment for this disease is based on the benefit of lowering LDLc and a healthy lifestyle. Actually, drug therapy is focused on using statins and combined therapy with ezetimibe and statins. This review highlights the recent progress made in genetics, diagnosis, and treatment for FH.

Keywords: APOB; LDL cholesterol; LDLR; PCSK9.