Physicians' Academy for Cardiovascular Education

FH mutation carriers at substantially increased CAD risk compared with non-carriers

Khera AV et al., JACC 2016

Diagnostic Yield of Sequencing Familial Hypercholesterolemia Genes in Patients with Severe Hypercholesterolemia

Khera AV, Won H-H, Peloso GM, et al.
JACC 2016; published online ahead of print


Familial Hypercholesterolemia (FH) is an autosomal dominant monogenic disorder that leads to severe elevation of LDL-C (≥190 mg/dl), due to impaired hepatic clearance of LDL-C [1,2]. However, such severe elevations of LDL-C are not always due to FH. The identification of an FH mutation in individuals with LDL-C ≥190 mg/dl is possible with the use of gene sequencing.

The extent to which FH mutations contribute to severe LDL-C elevations is unknown. This information would be useful to better understand the effectiveness of universal FH screening proposals [3,4]. Moreover, it is not clear whether the CAD risk differs among individuals with LDL-C ≥190 mg/dl, depending on whether they have an FH mutation or not. It is hypothesised that CAD risk may be greater if the LDL-C elevation is due to a monogenic mutation versus other causes, since a mutation leads to cumulative exposure to higher LDL-C levels during lifetime.
In this study, gene sequences of three FH genes (LDL receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9)) were analysed in 12 cohorts including > 26,000 participants to determine the diagnostic yield of gene sequencing to identify an FH mutation in severely hypercholesterolaemic individuals and the clinical impact of an FH mutation with regard to CAD risk within any given stratum of LDL-C levels.

Main results

  • Among 8,577 CAD-free control participants 430 had LDL-C ≥190 mg/dl; of these, 8 (1.9%) carried an FH mutation
  • Among 11,908 participants from 5 prospective cohorts 956 had LDL-C ≥190 mg/dl; of these 16 (1.7%) carried an FH mutation
  • Within any stratum of observed LDL-c, the risk of CAD was higher among FH mutation carriers when compared with non-carriers.
  • When compared to a reference group with LDL-C <130 mg/dl and no mutation: participants with LDL-C ≥190 mg/dl and no FH mutation had a 6-fold higher risk for CAD (OR: 6.0; 95%CI: 5.2–6.9), while participants with LDL-C ≥190 mg/dl and an FH mutation had a 22-fold higher risk for CAD (OR: 22.3; 95%CI: 10.7–53.2)


In a large cohort of individuals with LDL-C ≥190 mg/dl, genetic sequencing identified an FH mutation in <2%. However, for any given observed LDL-C level, FH mutation carriers are at substantially increased risk for CAD.
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2. Gidding SS, Ann Champagne M, de Ferranti SD, et al. The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association. Circulation. 2015 Dec 1;132(22):2167-92
3. Goldberg AC, Hopkins PN, Toth PP, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:1–8.
4. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia 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;34:3478-90a.