Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia

Abstract

Background About 7% of US adults have severe hypercholesterolemia (untreated LDL cholesterol ≥190 mg/dl). Such high LDL levels may be due to familial hypercholesterolemia (FH), a condition caused by a single mutation in any of three genes. Lifelong elevations in LDL cholesterol in FH mutation carriers may confer CAD risk beyond that captured by a single LDL cholesterol measurement. Objectives Assess the prevalence of a FH mutation among those with severe hypercholesterolemia and determine whether CAD risk varies according to mutation status beyond the observed LDL cholesterol. Methods Three genes causative for FH (LDLR, APOB, PCSK9) were sequenced in 26,025 participants from 7 case-control studies (5,540 CAD cases, 8,577 CAD-free controls) and 5 prospective cohort studies (11,908 participants). FH mutations included loss-of-function variants in LDLR, missense mutations in LDLR predicted to be damaging, and variants linked to FH in ClinVar, a clinical genetics database. Results Among 8,577 CAD-free control participants, 430 had LDL cholesterol ≥190 mg/dl; of these, only eight (1.9%) carried a FH mutation. Similarly, among 11,908 participants from 5 prospective cohorts, 956 had LDL cholesterol ≥190 mg/dl and of these, only 16 (1.7%) carried a FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers when compared with non-carriers. When compared to a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol ≥190 mg/dl and no FH mutation had six-fold higher risk for CAD (OR 6.0; 95%CI 5.2–6.9) whereas those with LDL cholesterol ≥190 mg/dl as well as a FH mutation demonstrated twenty-two fold increased risk (OR 22.3; 95%CI 10.7–53.2). Conclusions Among individuals with LDL cholesterol ≥190 mg/dl, gene sequencing identified a FH mutation in <2%. However, for any given observed LDL cholesterol, FH mutation carriers are at substantially increased risk for CAD.

Genetics: Implications for Prevention and Management of Coronary Artery Disease

“…They estimated that a decrease in 1 unit of LDL (38.7 mg/dl) since birth is associated with 54.5% reduction in cardiac events, which is 3-fold greater than that observed in clinical trials involving statin therapies given over shorter periods of time later in life (111). In a more recent study, individuals with LDL cholesterol >190 mg/dl on a single measure, who were carrying damaging mutations within FH genes (LDLR, APOB, and PCSK9), were found to be at 2 to 3 times higher risk of clinical CAD than individuals who were not carrying such mutations within every stratum of LDL (112). Furthermore, FH mutation carriers were found to have a higher cumulative exposure to LDL cholesterol than noncarriers in an analysis of participants with repeated measures over many years (112).…”

“…In a more recent study, individuals with LDL cholesterol >190 mg/dl on a single measure, who were carrying damaging mutations within FH genes (LDLR, APOB, and PCSK9), were found to be at 2 to 3 times higher risk of clinical CAD than individuals who were not carrying such mutations within every stratum of LDL (112). Furthermore, FH mutation carriers were found to have a higher cumulative exposure to LDL cholesterol than noncarriers in an analysis of participants with repeated measures over many years (112). These results reinforce the potential of early primary prevention of CAD, especially among those at very high lifetime risk at a young age, such as individuals suffering from FH or other polygenic causes of very elevated LDL levels.…”

Putting Into Perspective the Hazards of Untreated Familial Hypercholesterolemia

“…The estimates of cardiovascular disease and CAD incidence and associated hazard ratios by Kjaergaard et al herein1 are hampered by incompletely documented effects of prior treatment. The same may be said of the several other recent overall estimates of risk associated with genetically defined FH 2, 3, 4. None of the overall estimates of risk in FH mutation carriers versus noncarriers in these studies should be taken as risk associated with untreated FH.…”

“…New, objective screening projects in large US populations, with genetic testing done without regard to lipid levels, place the prevalence of FH mutation carriers (with mutations in LDLR , APOB , and PCSK9 ) in 3 different studies at 1 in 204,2 1 in 211,3 and 1 in 2224: more than double older estimates of 1 in 500. Similar estimates for prevalence of FH are reported for European populations 5, 6, 7, 8.…”

Coronary heart disease mortality in treated Familial Hypercholesterolaemia: Update of the UK Simon Broome FH Register

“…Patients with FH are exposed to elevated low density lipoprotein cholesterol (LDL-C) concentrations from birth and are at a higher risk of Coronary Heart Disease (CHD) for any given LDL-C concentration [4]. In the heterozygous condition the cumulative risk of CHD by the age of 60 years without effective treatment is at least 50% in men and about 30% in women [5e7].…”