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

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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.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.