FH mutation carriers at substantially increased CAD risk compared with non-carriersKhera 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.
- 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)
ConclusionIn 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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