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

• Published in: Microbial Drug Resistance
• Main Authors: Björnsson, Eythór, Thorgeirsson, Guðmundur, Helgadóttir, Anna, Thorleifsson, Guðmar, Sveinbjörnsson, Garðar, Kristmundsdóttir, Snaedís, Jónsson, Hákon, Jónasdóttir, Aðalbjörg, Jónasdóttir, Áslaug, Sigurðsson, Ásgeir, Guðnason, Thórarinn, Ólafsson, Ísleifur, Sigurðsson, Emil L, Sigurðardóttir, Ólöf, Viðarsson, Brynjar, Baldvinsson, Magnús, Bjarnason, Ragnar, Danielsen, Ragnar, Matthíasson, Stefán E, Thórarinsson, Björn L, Grétarsdóttir, Sólveig, Steinthórsdóttir, Valgerður, Halldórsson, Bjarni V, Andersen, Karl, Arnar, Davíð O, Jónsdóttir, Ingileif, Guðbjartsson, Daníel F, Hólm, Hilma, Thorsteinsdóttir, Unnur, Sulem, Patrick, Stefánsson, Kári
• Other Authors: 1deCODE genetics/Amgen, Inc, Reykjavík, Iceland (E.B., G. Thorgeirsson, A.H., G. Thorleifsson, G.S., S.K., H.J., Aðalbjörg Jónasdóttir, Áslaug Jónasdóttir, A.S., S.G., V.S., B.V.H., D.O.A., I.J., D.F.G., H.H., U.T., P.S., K.S.). 2Faculty of Medicine, University of Iceland, Reykjavík (E.B., E.L.S., R.B., K.A., D.O.A., I.J., U.T., K.S.). 3Department of Internal Medicine (E.B.), Landspítali-The National University Hospital of Iceland, Reykjavík. 4Division of Cardiology, Department of Internal Medicine (G. Thorgeirsson, R.D., K.A., D.O.A.), Landspítali-The National University Hospital of Iceland, Reykjavík. 5Icelandic Medical Center (Laeknasetrid), Reykjavík, Iceland (T.G.). 6Department of Clinical Biochemistry (I.O.), Landspítali-The National University Hospital of Iceland, Reykjavík. 7Development Centre for the Primary Care, Reykjavík, Iceland (E.L.S.). 8Department of Clinical Biochemistry, Akureyri Hospital, Iceland (O.S.). 9Department of Hematology (B.V.), Landspítali-The National University Hospital of Iceland, Reykjavík. 10The Laboratory in Mjódd, Reykjavík, Iceland (B.V.). 11Röntgen Domus, Reykjavík, Iceland (M.B.). 12Children's Medical Center (R.B.), Landspítali-The National University Hospital of Iceland, Reykjavík. 13Laekning, Medical Clinics, Reykjavík, Iceland (S.E.M.). 14Department of Neurology (B.L.T.), Landspítali-The National University Hospital of Iceland, Reykjavík. 15School of Engineering and Natural Sciences, University of Iceland, Reykjavík (D.F.G.).
• Format: Article in Journal/Newspaper
• Language: English
• Published: Lippincott Williams & Wilkins 2022
• Subjects: genetic screening; genetics; hypercholesterolemia; lipids; mutation; Hyperlipoproteinemia Type II; Genetic Predisposition to Disease; Genetic Association Studies; Iceland
• Online Access: http://hdl.handle.net/2336/622018; https://doi.org/10.1161/ATVBAHA.120.315904

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Download 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. Landspitali University Hospital Research Fund