title: Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease.
abstract: Sequence variants affecting blood lipids and coronary artery disease (CAD) may enhance understanding of the atherogenicity of lipid fractions. Using a large resource of whole-genome sequence data, we examined rare and low-frequency variants for association with non-HDL cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides in up to 119,146 Icelanders. We discovered 13 variants with large effects (within ANGPTL3, APOB, ABCA1, NR1H3, APOA1, LIPC, CETP, LDLR, and APOC1) and replicated 14 variants. Five variants within PCSK9, APOA1, ANGPTL4, and LDLR associate with CAD (33,090 cases and 236,254 controls). We used genetic risk scores for the lipid fractions to examine their causal relationship with CAD. The non-HDL cholesterol genetic risk score associates most strongly with CAD (P = 2.7 × 10(-28)), and no other genetic risk score associates with CAD after accounting for non-HDL cholesterol. The genetic risk score for non-HDL cholesterol confers CAD risk beyond that of LDL cholesterol (P = 5.5 × 10(-8)), suggesting that targeting atherogenic remnant cholesterol may reduce cardiovascular risk.
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Anna
authors.initials: A
authors.lastname: Helgadottir
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Solveig
authors.initials: S
authors.lastname: Gretarsdottir
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Eirikur
authors.initials: E
authors.lastname: Hjartarson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Asgeir
authors.initials: A
authors.lastname: Sigurdsson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Audur
authors.initials: A
authors.lastname: Magnusdottir
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Aslaug
authors.initials: A
authors.lastname: Jonasdottir
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Helgi
authors.initials: H
authors.lastname: Kristjansson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Patrick
authors.identifier: 0000-0001-7123-6123
authors.initials: P
authors.lastname: Sulem
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Asmundur
authors.initials: A
authors.lastname: Oddsson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Gardar
authors.initials: G
authors.lastname: Sveinbjornsson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Valgerdur
authors.initials: V
authors.lastname: Steinthorsdottir
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Thorunn
authors.initials: T
authors.lastname: Rafnar
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Gisli
authors.initials: G
authors.lastname: Masson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.|Department of Immunology, Landspítali-National University Hospital, Reykjavik, Iceland.
authors.forename: Ingileif
authors.initials: I
authors.lastname: Jonsdottir
authors.affiliation: Department of Clinical Biochemistry, Landspítali-National University Hospital, Reykjavik, Iceland.
authors.forename: Isleifur
authors.initials: I
authors.lastname: Olafsson
authors.affiliation: Laboratory in Mjódd (RAM), Reykjavik, Iceland.
authors.forename: Gudmundur I
authors.initials: GI
authors.lastname: Eyjolfsson
authors.affiliation: Department of Clinical Biochemistry, Akureyri Hospital, Akureyri, Iceland.
authors.forename: Olof
authors.initials: O
authors.lastname: Sigurdardottir
authors.affiliation: Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Maryam S
authors.initials: MS
authors.lastname: Daneshpour
authors.affiliation: Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Davood
authors.initials: D
authors.lastname: Khalili
authors.affiliation: Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Fereidoun
authors.initials: F
authors.lastname: Azizi
authors.affiliation: Department for Laboratory Medicine, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
authors.forename: Dorine W
authors.initials: DW
authors.lastname: Swinkels
authors.affiliation: Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, the Netherlands.
authors.forename: Lambertus
authors.initials: L
authors.lastname: Kiemeney
authors.affiliation: Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Arshed A
authors.initials: AA
authors.lastname: Quyyumi
authors.affiliation: Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Allan I
authors.initials: AI
authors.lastname: Levey
authors.affiliation: Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Riyaz S
authors.initials: RS
authors.lastname: Patel
authors.affiliation: Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Salim S
authors.initials: SS
authors.lastname: Hayek
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Landspítali-National University Hospital, Reykjavik, Iceland.
authors.forename: Ingibjorg J
authors.initials: IJ
authors.lastname: Gudmundsdottir
authors.affiliation: Faculty of Medicine, University of Iceland, Reykjavik, Iceland.|Division of Cardiology, Department of Internal Medicine, Landspítali-National University Hospital, Reykjavik, Iceland.
authors.forename: Gudmundur
authors.identifier: 0000-0002-7146-1395
authors.initials: G
authors.lastname: Thorgeirsson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Daniel F
authors.identifier: 0000-0002-5222-9857
authors.initials: DF
authors.lastname: Gudbjartsson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Division of Cardiology, Department of Internal Medicine, Landspítali-National University Hospital, Reykjavik, Iceland.
authors.forename: Hilma
authors.initials: H
authors.lastname: Holm
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D002784:Cholesterol / Q000097:blood*; D003324:Coronary Artery Disease / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008055:Lipids / Q000097:blood*; D014280:Triglycerides / Q000097:blood*
chemical_list: D008055:Lipids; D014280:Triglycerides; D002784:Cholesterol