Large-Scale Screening for Monogenic and Clinically Defined Familial Hypercholesterolemia in Iceland

Abstract

Objective: Familial hypercholesterolemia (FH) is traditionally defined as a monogenic disease characterized by severely elevated LDL-C (low-density lipoprotein cholesterol) levels. In practice, FH is commonly a clinical diagnosis without confirmation of a causative mutation. In this study, we sought to characterize and compare monogenic and clinically defined FH in a large sample of Icelanders. Approach and Results: We whole-genome sequenced 49 962 Icelanders and imputed the identified variants into an overall sample of 166 281 chip-genotyped Icelanders. We identified 20 FH mutations in LDLR, APOB, and PCSK9 with combined prevalence of 1 in 836. Monogenic FH was associated with severely elevated LDL-C levels and increased risk of premature coronary disease, aortic valve stenosis, and high burden of coronary atherosclerosis. We used a modified version of the Dutch Lipid Clinic Network criteria to screen for the clinical FH phenotype among living adult participants (N=79 058). Clinical FH was found in 2.2% of participants, of whom only 5.2% had monogenic FH. Mutation-negative clinical FH has a strong polygenic basis. Both individuals with monogenic FH and individuals with mutation-negative clinical FH were markedly undertreated with cholesterol-lowering medications and only a minority attained an LDL-C target of <2.6 mmol/L (<100 mg/dL; 11.0% and 24.9%, respectively) or <1.8 mmol/L (<70 mg/dL; 0.0% and 5.2%, respectively), as recommended for primary prevention by European Society of Cardiology/European Atherosclerosis Society cholesterol guidelines. Conclusions: Clinically defined FH is a relatively common phenotype that is explained by monogenic FH in only a minority of cases. Both monogenic and clinical FH confer high cardiovascular risk but are markedly undertreated.

Keywords: genetic screening; genetics; hypercholesterolemia; lipids; mutation.

Figure 1.

Monogenic familial hypercholesterolemia (FH) and LDL-C (low-density lipoprotein cholesterol) levels. A shows the distribution of the maximum documented LDL-C levels (maxLDL-C) in the subsample of 104 828 participants who had available LDL-C measurements. Individuals with monogenic FH are indicated with red (N=175) and FH mutation noncarriers with blue (N=104 653). B shows the distribution of maxLDL-C levels by FH mutation class. To convert LDL-C levels from mmol/L to mg/dL, multiply by 38.6.

Figure 2.

Cumulative lifetime exposure to LDL-C (low-density lipoprotein cholesterol). Shown is the estimated average lifetime cumulative exposure to LDL-C, in units of mmol/L years. Individuals with monogenic familial hypercholesterolemia (FH; N=175) are shown in red, and non-carriers (N=104 653) in blue. Here, LDL-C measurements were not adjusted for statin use and thus reflect actual exposure to LDL-C. To convert mmol/L years to mg/dL years, multiply by 38.6.

Figure 3.

Prescription patterns and effectiveness of cholesterol-lowering therapy in living individuals with monogenic familial hypercholesterolemia (FH; yellow, N=135) and mutation-negative clinical FH (blue, N=1508). Shown is the latest available LDL-C (low-density lipoprotein cholesterol) measurement (years 2004–2018) as a function of potency of the prescribed cholesterol-lowering therapy (ie, prescriptions of statins and ezetimibe) during the preceding year. Here, LDL-C values were not adjusted for statin use. Horizontal lines indicate the recommended target levels for primary prevention in FH according to the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) guidelines from 2016 (purple, <2.6 mmol/L) and 2019 (red, <1.8 mmol/L).

Figure 4.

Polygenic contribution to mutation-negative clinical familial hypercholesterolemia (FH). A shows the distribution of the LDL-C (low-density lipoprotein cholesterol) genetic score by clinical FH status according to a modified version of the Dutch Lipid Clinic Network criteria, excluding individuals with monogenic FH. Yellow indicates clinical FH (probable or definite FH, N=1564) and blue indicates controls (unlikely or possible FH, N=71 362). B shows odds ratios for clinical FH by percentiles of the LDL-C genetic score, given relative to the middle quintile (40–59th percentile). 95% CIs are presented.