Familial Hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism. It is a common autosomal dominant, or inherited, disease which affects the plasma clearance of LDL-cholesterol (LDL-C), resulting in premature onset of cardiovascular disease (CVD) and a higher mortality risk.₁-₃
Common genetic defects in FH are mutations in three genes encoding proteins involved in the uptake of LDL-C from the plasma: the low density lipoprotein receptor (LDLR) gene (prevalence of 1 in 500), the apo-lipoprotein B (ApoB) gene (prevalence of 1 in 1000) and the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene (prevalence of less than 1 in 2500).₁,₃
Patients who have one abnormal gene mutation are known as heterozygous. Heterozygous FH is a common genetic disorder, occurring in 1 person in 500 in most countries. Homozygous FH occurs when the patient has two abnormal gene mutations; however this is much rarer, with an occurrence of 1 in a million.₄
Early diagnosis of FH is crucial as by the time the heterozygous FH sufferer enters early adulthood they will have accumulated >20 years of continuous exposure to build up of fatty or lipid masses in arterial walls and are at a hundred-fold greater risk of a heart attack than other young people. Patients with homozygous FH are at such high risk that they may not live beyond childhood into early adulthood.₄
The UK National Institute for Health and Clinical Excellence (NICE) guidelines published in 2008 recommend that all FH patients be offered a DNA test to confirm the diagnosis and that identified mutations should be used as the basis for cascade testing of first-degree relatives of index cases. Patients newly identified by such screening can then be offered treatment to reduce the risk of premature cardiac events.₁
Only few countries currently have national genetic screening programs for FH despite evidence demonstrating that implementing such a program is highly cost-effective, particularly for cascade testing of known index cases as roughly 50% will have inherited the mutation.₅-₆
Several validation studies were completed using FH samples, with both blinded and un-blinded samples assessed. Total correlation of 98% was observed when using the Familial Hypercholesterolemia Arrays I & II.
₁Futema, M., et al. Analysis of the frequency and spectrum of mutations recognised to cause FH in routine clinical practice in a UK specialist hospital lipid clinic. Atherosclerosis 2013; 229(1): 161-168.
₂ Williams, R.R., et al. Diagnosing Heterozygous Familial Hypercholesterolemia Using New Practical Criteria Validated by Molecular Genetics. American Journal of Cardiology 1993; 72:171-176.
₃Rader, D.J., Cohen J., Hobbs, H.H. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. Journal of Clinical Investigation 2003; 111:1795-1803.
₄ Quereshi, N., Humphries, S.E., Seed, M., Rowlands, P., Minhas, R. Identification and management of familial hypercholesterolaemia: what does it mean to primary care? Br J Gen Pract 2009; 59: 773-778.
₅ Nordestgaard, B.G. et al. Familial hypercholesterolemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease. Consensus Statement of the European Atherosclerosis Society.
Eur Heart J 2013. Available online: http://eurheartj.oxfordjournals.org/content/early/2013/08/15/eurheartj.eht273.full.pdf+html.