Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease

Anna Helgadottir; Solveig Gretarsdottir; Gudmar Thorleifsson; Eirikur Hjartarson; Asgeir Sigurdsson; Audur Magnusdottir; Aslaug Jonasdottir; Helgi Kristjansson; Patrick Sulem; Asmundur Oddsson; Gardar Sveinbjornsson; Valgerdur Steinthorsdottir; Thorunn Rafnar; Gisli Masson; Ingileif Jonsdottir; Isleifur Olafsson; Gudmundur I. Eyjolfsson; Olof Sigurdardottir; Maryam S. Daneshpour; Davood Khalili; Fereidoun Azizi; Dorine W. Swinkels; Lambertus Kiemeney; Arshed A. Quyyumi; Allan I. Levey; Riyaz S. Patel; Salim S. Hayek; Ingibjorg J. Gudmundsdottir; Gudmundur Thorgeirsson; Unnur Thorsteinsdottir; Daniel F. Gudbjartsson; Hilma Holm; Kari Stefansson

doi:10.1038/ng.3561

Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease

Anna Helgadottir, Solveig Gretarsdottir, Gudmar Thorleifsson, Eirikur Hjartarson, Asgeir Sigurdsson, Audur Magnusdottir, Aslaug Jonasdottir, Helgi Kristjansson, Patrick Sulem, Asmundur Oddsson, Gardar Sveinbjornsson, Valgerdur Steinthorsdottir, Thorunn Rafnar, Gisli Masson, Ingileif Jonsdottir, Isleifur Olafsson, Gudmundur I. Eyjolfsson, Olof Sigurdardottir, Maryam S. Daneshpour, Davood KhaliliFereidoun Azizi, Dorine W. Swinkels, Lambertus Kiemeney, Arshed A. Quyyumi, Allan I. Levey, Riyaz S. Patel, Salim S. Hayek, Ingibjorg J. Gudmundsdottir, Gudmundur Thorgeirsson, Unnur Thorsteinsdottir, Daniel F. Gudbjartsson, Hilma Holm, Kari Stefansson

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	634-639
Number of pages	6
Journal	Nature Genetics
Volume	48
Issue number	6
DOIs	https://doi.org/10.1038/ng.3561
State	Published - Jun 1 2016
Externally published	Yes

ASJC Scopus subject areas

Genetics

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Helgadottir, A., Gretarsdottir, S., Thorleifsson, G., Hjartarson, E., Sigurdsson, A., Magnusdottir, A., Jonasdottir, A., Kristjansson, H., Sulem, P., Oddsson, A., Sveinbjornsson, G., Steinthorsdottir, V., Rafnar, T., Masson, G., Jonsdottir, I., Olafsson, I., Eyjolfsson, G. I., Sigurdardottir, O., Daneshpour, M. S., ... Stefansson, K. (2016). Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease. Nature Genetics, 48(6), 634-639. https://doi.org/10.1038/ng.3561

Helgadottir, A, Gretarsdottir, S, Thorleifsson, G, Hjartarson, E, Sigurdsson, A, Magnusdottir, A, Jonasdottir, A, Kristjansson, H, Sulem, P, Oddsson, A, Sveinbjornsson, G, Steinthorsdottir, V, Rafnar, T, Masson, G, Jonsdottir, I, Olafsson, I, Eyjolfsson, GI, Sigurdardottir, O, Daneshpour, MS, Khalili, D, Azizi, F, Swinkels, DW, Kiemeney, L, Quyyumi, AA, Levey, AI, Patel, RS, Hayek, SS, Gudmundsdottir, IJ, Thorgeirsson, G, Thorsteinsdottir, U, Gudbjartsson, DF, Holm, H & Stefansson, K 2016, 'Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease', Nature Genetics, vol. 48, no. 6, pp. 634-639. https://doi.org/10.1038/ng.3561

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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.",

author = "Anna Helgadottir and Solveig Gretarsdottir and Gudmar Thorleifsson and Eirikur Hjartarson and Asgeir Sigurdsson and Audur Magnusdottir and Aslaug Jonasdottir and Helgi Kristjansson and Patrick Sulem and Asmundur Oddsson and Gardar Sveinbjornsson and Valgerdur Steinthorsdottir and Thorunn Rafnar and Gisli Masson and Ingileif Jonsdottir and Isleifur Olafsson and Eyjolfsson, {Gudmundur I.} and Olof Sigurdardottir and Daneshpour, {Maryam S.} and Davood Khalili and Fereidoun Azizi and Swinkels, {Dorine W.} and Lambertus Kiemeney and Quyyumi, {Arshed A.} and Levey, {Allan I.} and Patel, {Riyaz S.} and Hayek, {Salim S.} and Gudmundsdottir, {Ingibjorg J.} and Gudmundur Thorgeirsson and Unnur Thorsteinsdottir and Gudbjartsson, {Daniel F.} and Hilma Holm and Kari Stefansson",

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T1 - Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease

AU - Helgadottir, Anna

AU - Gretarsdottir, Solveig

AU - Thorleifsson, Gudmar

AU - Hjartarson, Eirikur

AU - Sigurdsson, Asgeir

AU - Magnusdottir, Audur

AU - Jonasdottir, Aslaug

AU - Kristjansson, Helgi

AU - Sulem, Patrick

AU - Oddsson, Asmundur

AU - Sveinbjornsson, Gardar

AU - Steinthorsdottir, Valgerdur

AU - Rafnar, Thorunn

AU - Masson, Gisli

AU - Jonsdottir, Ingileif

AU - Olafsson, Isleifur

AU - Eyjolfsson, Gudmundur I.

AU - Sigurdardottir, Olof

AU - Daneshpour, Maryam S.

AU - Khalili, Davood

AU - Azizi, Fereidoun

AU - Swinkels, Dorine W.

AU - Kiemeney, Lambertus

AU - Quyyumi, Arshed A.

AU - Levey, Allan I.

AU - Patel, Riyaz S.

AU - Hayek, Salim S.

AU - Gudmundsdottir, Ingibjorg J.

AU - Thorgeirsson, Gudmundur

AU - Thorsteinsdottir, Unnur

AU - Gudbjartsson, Daniel F.

AU - Holm, Hilma

AU - Stefansson, Kari

PY - 2016/6/1

Y1 - 2016/6/1

N2 - 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.

AB - 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.

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Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease

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