{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:17:42Z","timestamp":1790612262682,"version":"4.1.0"},"reference-count":60,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","license":[{"start":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T00:00:00Z","timestamp":1633046400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:sec>\n            <jats:title>Objective:<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results:<\/jats:title>\n            <jats:p>\n              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\n              <jats:italic>LDLR<\/jats:italic>\n              ,\n              <jats:italic>APOB<\/jats:italic>\n              , and\n              <jats:italic>PCSK9<\/jats:italic>\n              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\u2009058). 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 &lt;2.6 mmol\/L (&lt;100 mg\/dL; 11.0% and 24.9%, respectively) or &lt;1.8 mmol\/L (&lt;70 mg\/dL; 0.0% and 5.2%, respectively), as recommended for primary prevention by European Society of Cardiology\/European Atherosclerosis Society cholesterol guidelines.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.120.315904","type":"journal-article","created":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T09:02:23Z","timestamp":1629363743000},"page":"2616-2628","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":25,"title":["Large-Scale Screening for Monogenic and Clinically Defined Familial Hypercholesterolemia in Iceland"],"prefix":"10.1161","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0979-261X","authenticated-orcid":true,"given":"Eyth\u00f3r","family":"Bj\u00f6rnsson","sequence":"first","affiliation":[{"name":"deCODE genetics\/Amgen, Inc, Reykjav\u00edk, Iceland (E.B., G. Thorgeirsson, A.H., G. Thorleifsson, G.S., S.K., H.J., A\u00f0albj\u00f6rg J\u00f3nasd\u00f3ttir, \u00c1slaug J\u00f3nasd\u00f3ttir, 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.)."},{"name":"Faculty of Medicine, University of Iceland, Reykjav\u00edk (E.B., E.L.S., R.B., K.A., D.O.A., I.J., U.T., K.S.)."},{"name":"Department of Internal Medicine (E.B.), Landsp\u00edtali-The National University Hospital of Iceland, Reykjav\u00edk."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7146-1395","authenticated-orcid":true,"given":"Gu\u00f0mundur","family":"Thorgeirsson","sequence":"additional","affiliation":[{"name":"deCODE genetics\/Amgen, Inc, Reykjav\u00edk, Iceland (E.B., G. Thorgeirsson, A.H., G. Thorleifsson, G.S., S.K., H.J., A\u00f0albj\u00f6rg J\u00f3nasd\u00f3ttir, \u00c1slaug J\u00f3nasd\u00f3ttir, 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.)."},{"name":"Division of Cardiology, Department of Internal Medicine (G. Thorgeirsson, R.D., K.A., D.O.A.), Landsp\u00edtali-The National University Hospital of Iceland, Reykjav\u00edk."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1806-2467","authenticated-orcid":true,"given":"Anna","family":"Helgad\u00f3ttir","sequence":"additional","affiliation":[{"name":"deCODE genetics\/Amgen, Inc, Reykjav\u00edk, Iceland (E.B., G. Thorgeirsson, A.H., G. Thorleifsson, G.S., S.K., H.J., A\u00f0albj\u00f6rg J\u00f3nasd\u00f3ttir, \u00c1slaug J\u00f3nasd\u00f3ttir, 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4623-9087","authenticated-orcid":true,"given":"Gu\u00f0mar","family":"Thorleifsson","sequence":"additional","affiliation":[{"name":"deCODE genetics\/Amgen, Inc, Reykjav\u00edk, Iceland (E.B., G. Thorgeirsson, A.H., G. Thorleifsson, G.S., S.K., H.J., A\u00f0albj\u00f6rg J\u00f3nasd\u00f3ttir, \u00c1slaug J\u00f3nasd\u00f3ttir, 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gar\u00f0ar","family":"Sveinbj\u00f6rnsson","sequence":"additional","affiliation":[{"name":"deCODE genetics\/Amgen, Inc, Reykjav\u00edk, Iceland (E.B., G. Thorgeirsson, A.H., G. Thorleifsson, G.S., S.K., H.J., A\u00f0albj\u00f6rg J\u00f3nasd\u00f3ttir, \u00c1slaug J\u00f3nasd\u00f3ttir, 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Snaed\u00eds","family":"Kristmundsd\u00f3ttir","sequence":"additional","affiliation":[{"name":"deCODE genetics\/Amgen, Inc, Reykjav\u00edk, Iceland (E.B., G. Thorgeirsson, A.H., G. Thorleifsson, G.S., S.K., H.J., A\u00f0albj\u00f6rg J\u00f3nasd\u00f3ttir, \u00c1slaug J\u00f3nasd\u00f3ttir, 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e1kon","family":"J\u00f3nsson","sequence":"additional","affiliation":[{"name":"deCODE genetics\/Amgen, Inc, Reykjav\u00edk, Iceland (E.B., G. Thorgeirsson, A.H., G. Thorleifsson, G.S., S.K., H.J., A\u00f0albj\u00f6rg J\u00f3nasd\u00f3ttir, \u00c1slaug J\u00f3nasd\u00f3ttir, 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A\u00f0albj\u00f6rg","family":"J\u00f3nasd\u00f3ttir","sequence":"additional","affiliation":[{"name":"deCODE genetics\/Amgen, Inc, Reykjav\u00edk, Iceland (E.B., G. Thorgeirsson, A.H., G. Thorleifsson, G.S., S.K., H.J., A\u00f0albj\u00f6rg J\u00f3nasd\u00f3ttir, \u00c1slaug J\u00f3nasd\u00f3ttir, 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1slaug","family":"J\u00f3nasd\u00f3ttir","sequence":"additional","affiliation":[{"name":"deCODE genetics\/Amgen, Inc, Reykjav\u00edk, Iceland (E.B., G. Thorgeirsson, A.H., G. Thorleifsson, G.S., S.K., H.J., A\u00f0albj\u00f6rg J\u00f3nasd\u00f3ttir, \u00c1slaug J\u00f3nasd\u00f3ttir, 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1sgeir","family":"Sigur\u00f0sson","sequence":"additional","affiliation":[{"name":"deCODE genetics\/Amgen, Inc, Reykjav\u00edk, Iceland (E.B., G. Thorgeirsson, A.H., G. Thorleifsson, G.S., S.K., H.J., A\u00f0albj\u00f6rg J\u00f3nasd\u00f3ttir, \u00c1slaug J\u00f3nasd\u00f3ttir, 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Th\u00f3rarinn","family":"Gu\u00f0nason","sequence":"additional","affiliation":[{"name":"Icelandic Medical Center (Laeknasetrid), Reykjav\u00edk, Iceland (T.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00cdsleifur","family":"\u00d3lafsson","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry (I.O.), Landsp\u00edtali-The National University Hospital of Iceland, Reykjav\u00edk."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emil L.","family":"Sigur\u00f0sson","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Iceland, Reykjav\u00edk (E.B., E.L.S., R.B., K.A., D.O.A., I.J., U.T., K.S.)."},{"name":"Development Centre for the Primary Care, Reykjav\u00edk, Iceland (E.L.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5347-1226","authenticated-orcid":true,"given":"\u00d3l\u00f6f","family":"Sigur\u00f0ard\u00f3ttir","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, Akureyri Hospital, Iceland (O.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brynjar","family":"Vi\u00f0arsson","sequence":"additional","affiliation":[{"name":"Department of Hematology (B.V.), Landsp\u00edtali-The National University Hospital of Iceland, Reykjav\u00edk."},{"name":"The Laboratory in Mj\u00f3dd, Reykjav\u00edk, Iceland (B.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magn\u00fas","family":"Baldvinsson","sequence":"additional","affiliation":[{"name":"R\u00f6ntgen Domus, Reykjav\u00edk, Iceland (M.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7121-9689","authenticated-orcid":true,"given":"Ragnar","family":"Bjarnason","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Iceland, Reykjav\u00edk (E.B., E.L.S., R.B., K.A., D.O.A., I.J., U.T., K.S.)."},{"name":"Children\u2019s Medical Center (R.B.), Landsp\u00edtali-The National University Hospital of Iceland, Reykjav\u00edk."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ragnar","family":"Danielsen","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine (G. Thorgeirsson, R.D., K.A., D.O.A.), Landsp\u00edtali-The National University Hospital of Iceland, Reykjav\u00edk."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stef\u00e1n E.","family":"Matth\u00edasson","sequence":"additional","affiliation":[{"name":"Laekning, Medical Clinics, Reykjav\u00edk, Iceland (S.E.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn L.","family":"Th\u00f3rarinsson","sequence":"additional","affiliation":[{"name":"Department of Neurology (B.L.T.), Landsp\u00edtali-The National University Hospital of Iceland, Reykjav\u00edk."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00f3lveig","family":"Gr\u00e9tarsd\u00f3ttir","sequence":"additional","affiliation":[{"name":"deCODE genetics\/Amgen, Inc, Reykjav\u00edk, Iceland (E.B., G. Thorgeirsson, A.H., G. Thorleifsson, G.S., S.K., H.J., A\u00f0albj\u00f6rg J\u00f3nasd\u00f3ttir, \u00c1slaug J\u00f3nasd\u00f3ttir, 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1846-6274","authenticated-orcid":true,"given":"Valger\u00f0ur","family":"Steinth\u00f3rsd\u00f3ttir","sequence":"additional","affiliation":[{"name":"deCODE genetics\/Amgen, Inc, Reykjav\u00edk, Iceland (E.B., G. Thorgeirsson, A.H., G. Thorleifsson, G.S., S.K., H.J., A\u00f0albj\u00f6rg J\u00f3nasd\u00f3ttir, \u00c1slaug J\u00f3nasd\u00f3ttir, 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0756-0767","authenticated-orcid":true,"given":"Bjarni V.","family":"Halld\u00f3rsson","sequence":"additional","affiliation":[{"name":"deCODE genetics\/Amgen, Inc, Reykjav\u00edk, Iceland (E.B., G. Thorgeirsson, A.H., G. Thorleifsson, G.S., S.K., H.J., A\u00f0albj\u00f6rg J\u00f3nasd\u00f3ttir, \u00c1slaug J\u00f3nasd\u00f3ttir, 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5473-7794","authenticated-orcid":true,"given":"Karl","family":"Andersen","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Iceland, Reykjav\u00edk (E.B., E.L.S., R.B., K.A., D.O.A., I.J., U.T., K.S.)."},{"name":"Division of Cardiology, Department of Internal Medicine (G. Thorgeirsson, R.D., K.A., D.O.A.), Landsp\u00edtali-The National University Hospital of Iceland, Reykjav\u00edk."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dav\u00ed\u00f0 O.","family":"Arnar","sequence":"additional","affiliation":[{"name":"deCODE genetics\/Amgen, Inc, Reykjav\u00edk, Iceland (E.B., G. Thorgeirsson, A.H., G. Thorleifsson, G.S., S.K., H.J., A\u00f0albj\u00f6rg J\u00f3nasd\u00f3ttir, \u00c1slaug J\u00f3nasd\u00f3ttir, 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.)."},{"name":"Faculty of Medicine, University of Iceland, Reykjav\u00edk (E.B., E.L.S., R.B., K.A., D.O.A., I.J., U.T., K.S.)."},{"name":"Division of Cardiology, Department of Internal Medicine (G. Thorgeirsson, R.D., K.A., D.O.A.), Landsp\u00edtali-The National University Hospital of Iceland, Reykjav\u00edk."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingileif","family":"J\u00f3nsd\u00f3ttir","sequence":"additional","affiliation":[{"name":"deCODE genetics\/Amgen, Inc, Reykjav\u00edk, Iceland (E.B., G. Thorgeirsson, A.H., G. 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