1. Large-Scale Screening for Monogenic and Clinically Defined Familial Hypercholesterolemia in Iceland
- Author
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Emil L. Sigurðsson, Unnur Thorsteinsdottir, Valgerður Steinthórsdóttir, Davíð O. Arnar, Karl Andersen, Ásgeir Sigurðsson, G. Thorleifsson, Magnús Baldvinsson, Patrick Sulem, Stefan E Matthiasson, Kari Stefansson, G Sveinbjörnsson, Aslaug Jonasdottir, Ólöf Sigurðardóttir, Ragnar Bjarnason, Aðalbjörg Jónasdóttir, Ingileif Jonsdottir, Thórarinn Guðnason, Eythór Björnsson, Bjorn L. Thorarinsson, Isleifur Olafsson, Solveig Gretarsdottir, Ragnar Danielsen, Brynjar Viðarsson, Snaedis Kristmundsdottir, Daníel F. Guðbjartsson, Hakon Jonsson, Anna Helgadottir, Bjarni V. Halldorsson, Guðmundur Thorgeirsson, and Hilma Holm
- Subjects
Scale (ratio) ,Familial hypercholesterolemia ,Monogenic disease ,lipids ,Hyperlipoproteinemia Type II ,medicine ,Prevalence ,Humans ,genetics ,Registries ,Lipoprotein cholesterol ,Genetics ,hypercholesterolemia ,business.industry ,genetic screening ,Cholesterol, LDL ,medicine.disease ,Mutation (genetic algorithm) ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,mutation ,Cardiology and Cardiovascular Medicine ,business ,Clinical and Population Studies - Abstract
Supplemental Digital Content is available in the text., 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
- Published
- 2021