Open AccessVariants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease
Author(s) -
Anna Helgadóttir,
Sólveig Grétarsdóttir,
Guðmar Þorleifsson,
Eirikur Hjartarson,
Ásgeir Sigurðsson,
Audur Magnusdottir,
Áslaug Jónasdóttir,
Helgi Kristjansson,
Patrick Sulem,
Ásmundur Oddsson,
Garðar Sveinbjörnsson,
Valgerður Steinthórsdóttir,
Thorunn Rafnar,
Gísli Másson,
Ingileif Jónsdóttir,
Ísleifur Ólafsson,
Gudmundur I. Eyjolfsson,
Ólöf Sigurðardóttir,
Maryam S. Daneshpour,
Davood Khalili,
Fereidoun Azizi,
Dorine W. Swinkels,
Lambertus A. Kiemeney,
Arshed A Quyyumi,
Aĺlan I. Levey,
Riyaz Patel,
Salim S. Hayek,
Ingibjörg Guðmundsdóttir,
Guðmundur Þorgeirsson,
Unnur Þorsteinsdóttir,
Daníel F. Guðbjartsson,
Hilma Hólm,
Kāri Stefánsson
Publication year - 2016
Publication title -
nature genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 18.861
H-Index - 573
eISSN - 1546-1718
pISSN - 1061-4036
DOI - 10.1038/ng.3561
Subject(s) - cholesterol , biology , medicine , apolipoprotein b , abca1 , coronary artery disease , pcsk9 , lipoprotein , triglyceride , endocrinology , genetics , ldl receptor , gene , transporter
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.