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

Autor:	Björnsson E; deCODE 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.).; Faculty of Medicine, University of Iceland, Reykjavík (E.B., E.L.S., R.B., K.A., D.O.A., I.J., U.T., K.S.).; Department of Internal Medicine (E.B.), Landspítali-The National University Hospital of Iceland, Reykjavík., Thorgeirsson G; deCODE 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.).; Division of Cardiology, Department of Internal Medicine (G. Thorgeirsson, R.D., K.A., D.O.A.), Landspítali-The National University Hospital of Iceland, Reykjavík., Helgadóttir A; deCODE 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.)., Thorleifsson G; deCODE 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.)., Sveinbjörnsson G; deCODE 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.)., Kristmundsdóttir S; deCODE 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.)., Jónsson H; deCODE 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.)., Jónasdóttir A; deCODE 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.)., Jónasdóttir Á; deCODE 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.)., Sigurðsson Á; deCODE 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.)., Guðnason T; Icelandic Medical Center (Laeknasetrid), Reykjavík, Iceland (T.G.)., Ólafsson Í; Department of Clinical Biochemistry (I.O.), Landspítali-The National University Hospital of Iceland, Reykjavík., Sigurðsson EL; Faculty of Medicine, University of Iceland, Reykjavík (E.B., E.L.S., R.B., K.A., D.O.A., I.J., U.T., K.S.).; Development Centre for the Primary Care, Reykjavík, Iceland (E.L.S.)., Sigurðardóttir Ó; Department of Clinical Biochemistry, Akureyri Hospital, Iceland (O.S.)., Viðarsson B; Department of Hematology (B.V.), Landspítali-The National University Hospital of Iceland, Reykjavík.; The Laboratory in Mjódd, Reykjavík, Iceland (B.V.)., Baldvinsson M; Röntgen Domus, Reykjavík, Iceland (M.B.)., Bjarnason R; Faculty of Medicine, University of Iceland, Reykjavík (E.B., E.L.S., R.B., K.A., D.O.A., I.J., U.T., K.S.).; Children's Medical Center (R.B.), Landspítali-The National University Hospital of Iceland, Reykjavík., Danielsen R; Division of Cardiology, Department of Internal Medicine (G. Thorgeirsson, R.D., K.A., D.O.A.), Landspítali-The National University Hospital of Iceland, Reykjavík., Matthíasson SE; Laekning, Medical Clinics, Reykjavík, Iceland (S.E.M.)., Thórarinsson BL; Department of Neurology (B.L.T.), Landspítali-The National University Hospital of Iceland, Reykjavík., Grétarsdóttir S; deCODE 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.)., Steinthórsdóttir V; deCODE 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.)., Halldórsson BV; deCODE 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.)., Andersen K; Faculty of Medicine, University of Iceland, Reykjavík (E.B., E.L.S., R.B., K.A., D.O.A., I.J., U.T., K.S.).; Division of Cardiology, Department of Internal Medicine (G. Thorgeirsson, R.D., K.A., D.O.A.), Landspítali-The National University Hospital of Iceland, Reykjavík., Arnar DO; deCODE 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.).; Faculty of Medicine, University of Iceland, Reykjavík (E.B., E.L.S., R.B., K.A., D.O.A., I.J., U.T., K.S.).; Division of Cardiology, Department of Internal Medicine (G. Thorgeirsson, R.D., K.A., D.O.A.), Landspítali-The National University Hospital of Iceland, Reykjavík., Jónsdóttir I; deCODE 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.).; Faculty of Medicine, University of Iceland, Reykjavík (E.B., E.L.S., R.B., K.A., D.O.A., I.J., U.T., K.S.)., Guðbjartsson DF; deCODE 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.).; School of Engineering and Natural Sciences, University of Iceland, Reykjavík (D.F.G.)., Hólm H; deCODE 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.)., Thorsteinsdóttir U; deCODE 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.).; Faculty of Medicine, University of Iceland, Reykjavík (E.B., E.L.S., R.B., K.A., D.O.A., I.J., U.T., K.S.)., Sulem P; deCODE 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.)., Stefánsson K; deCODE 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.).; Faculty of Medicine, University of Iceland, Reykjavík (E.B., E.L.S., R.B., K.A., D.O.A., I.J., U.T., K.S.).
Jazyk:	angličtina
Zdroj:	Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2021 Oct; Vol. 41 (10), pp. 2616-2628. Date of Electronic Publication: 2021 Aug 19.
DOI:	10.1161/ATVBAHA.120.315904
Abstrakt:	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.
Databáze:	MEDLINE
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