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

被引：209

作者：

Helgadottir, Anna ^{[1
,2
]}

Gretarsdottir, Solveig ^{[1
]}

Thorleifsson, Gudmar ^{[1
]}

Hjartarson, Eirikur ^{[1
]}

Sigurdsson, Asgeir ^{[1
]}

Magnusdottir, Audur ^{[1
]}

Jonasdottir, Aslaug ^{[1
]}

Kristjansson, Helgi ^{[1
]}

Sulem, Patrick ^{[1
]}

Oddsson, Asmundur ^{[1
]}

Sveinbjornsson, Gardar ^{[1
]}

Steinthorsdottir, Valgerdur ^{[1
]}

Rafnar, Thorunn ^{[1
]}

Masson, Gisli ^{[1
]}

Jonsdottir, Ingileif ^{[1
,2
,3
]}

Olafsson, Isleifur ^{[4
]}

Eyjolfsson, Gudmundur I. ^{[5
]}

Sigurdardottir, Olof ^{[6
]}

Daneshpour, Maryam S. ^{[7
]}

Khalili, Davood ^{[8
]}

Azizi, Fereidoun ^{[9
]}

Swinkels, Dorine W. ^{[10
]}

Kiemeney, Lambertus ^{[11
]}

Quyyumi, Arshed A. ^{[12
]}

Levey, Allan I. ^{[12
]}

Patel, Riyaz S. ^{[12
]}

Hayek, Salim S. ^{[12
]}

Gudmundsdottir, Ingibjorg J. ^{[13
]}

Thorgeirsson, Gudmundur ^{[2
,13
]}

Thorsteinsdottir, Unnur ^{[1
,2
]}

Gudbjartsson, Daniel F. ^{[1
,14
]}

Holm, Hilma ^{[1
,13
]}

Stefansson, Kari ^{[1
,2
]}

机构：

[1] Amgen Inc, deCODE Genet, Reykjavik, Iceland

[2] Univ Iceland, Fac Med, Reykjavik, Iceland

[3] Landspitali Natl Univ Hosp, Dept Immunol, Reykjavik, Iceland

[4] Landspitali Natl Univ Hosp, Dept Clin Biochem, Reykjavik, Iceland

[5] Lab Mjodd RAM, Reykjavik, Iceland

[6] Akureyri Hosp, Dept Clin Biochem, Akureyri, Iceland

[7] Shahid Beheshti Univ Med Sci, Res Inst Endocrine Sci, Cellular & Mol Endocrine Res Ctr, Tehran, Iran

[8] Shahid Beheshti Univ Med Sci, Prevent Metab Disorders Res Ctr, Res Inst Endocrine Sci, Tehran, Iran

[9] Shahid Beheshti Univ Med Sci, Endocrine Res Ctr, Res Inst Endocrine Sci, Tehran, Iran

[10] Radboud Univ Nijmegen, Dept Lab Med, Med Ctr, Radboud Inst Mol Life Sci, NL-6525 ED Nijmegen, Netherlands

[11] Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[12] Emory Univ, Sch Med, Atlanta, GA USA

[13] Landspitali Natl Univ Hosp, Dept Internal Med, Div Cardiol, Reykjavik, Iceland

[14] Univ Iceland, Sch Engn & Nat Sci, Reykjavik, Iceland

来源：

NATURE GENETICS | 2016年 / 48卷 / 06期

关键词：

SEQUENCING IDENTIFIES RARE; LOW-FREQUENCY; GENETIC-VARIANTS; HEART-DISEASE; RISK; ASSOCIATION; MUTATIONS; PLASMA;

D O I：

10.1038/ng.3561

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 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 x 10(-8)), suggesting that targeting atherogenic remnant cholesterol may reduce cardiovascular risk.

引用

页码：634 / +

页数：8

共 42 条

[1] Prevention of non-communicable disease in a population in nutrition transition: Tehran Lipid and Glucose Study phase II [J].

Azizi, Fereidoun ;

Ghanbarian, Arash ;

Momenan, Amir Abbas ;

Hadaegh, Farzad ;

Mirmiran, Parvin ;

Hedayati, Mehdi ;

Mehrabi, Yadollah ;

Zahedi-Asl, Saleh .

TRIALS, 2009, 10

[2] Effects of torcetrapib in patients at high risk for coronary events [J].

Barter, Philip J. ;

Caulfield, Mark ;

Eriksson, Mats ;

Grundy, Scott M. ;

Kastelein, John J. P. ;

Komajda, Michel ;

Lopez-Sendon, Jose ;

Mosca, Lori ;

Tardif, Jean-Claude ;

Waters, David D. ;

Shear, Charles L. ;

Revkin, James H. ;

Buhr, Kevin A. ;

Fisher, Marian R. ;

Tall, Alan R. ;

Brewer, Bryan .

NEW ENGLAND JOURNAL OF MEDICINE, 2007, 357 (21) :2109-2122

[3] Association of apolipoprotein E genotypes with lipid levels and coronary risk [J].

Bennet, Anna M. ;

Di Angelantonio, Emanuele ;

Ye, Zheng ;

Wensley, Frances ;

Dahlin, Anette ;

Ahlbom, Anders ;

Keavney, Bernard ;

Collins, Rory ;

Wiman, Bjoern ;

de Faire, Ulf ;

Danesh, John .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2007, 298 (11) :1300-1311

[4] Severe hypertriglyceridemia in human APOC1 transgenic mice is caused by apoC-I-induced inhibition of LPL [J].

Berbée, JFP ;

van der Hoogt, CC ;

Sundararaman, D ;

Havekes, LM ;

Rensen, PCN .

JOURNAL OF LIPID RESEARCH, 2005, 46 (02) :297-306

[5] Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression [J].

Bowden, Jack ;

Smith, George Davey ;

Burgess, Stephen .

INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, 2015, 44 (02) :512-525

[6] A RECEPTOR-MEDIATED PATHWAY FOR CHOLESTEROL HOMEOSTASIS [J].

BROWN, MS ;

GOLDSTEIN, JL .

SCIENCE, 1986, 232 (4746) :34-47

[7] Human genetics of HDL: Insight into particle metabolism and function [J].

Brunham, Liam R. ;

Hayden, Michael R. .

PROGRESS IN LIPID RESEARCH, 2015, 58 :14-25

[8] Genetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease [J].

Clarke, Robert ;

Peden, John F. ;

Hopewell, Jemma C. ;

Kyriakou, Theodosios ;

Goel, Anuj ;

Heath, Simon C. ;

Parish, Sarah ;

Barlera, Simona ;

Franzosi, Maria Grazia ;

Rust, Stephan ;

Bennett, Derrick ;

Silveira, Angela ;

Malarstig, Anders ;

Green, Fiona R. ;

Lathrop, Mark ;

Gigante, Bruna ;

Leander, Karin ;

de Faire, Ulf ;

Seedorf, Udo ;

Hamsten, Anders ;

Collins, Rory ;

Watkins, Hugh ;

Farrall, Martin .

NEW ENGLAND JOURNAL OF MEDICINE, 2009, 361 (26) :2518-2528

[9] Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease [J].

Crosby, Jacy ;

Peloso, Gina M. ;

Auer, Paul L. ;

Crosslin, David R. ;

Stitziel, Nathan O. ;

Lange, Leslie A. ;

Lu, Yingchang ;

Tang, Zheng-zheng ;

Zhang, He ;

Hindy, George ;

Masca, Nicholas ;

Stirrups, Kathleen ;

Kanoni, Stavroula ;

Do, Ron ;

Jun, Goo ;

Hu, Youna ;

Kang, Hyun Min ;

Xue, Chenyi ;

Goel, Anuj ;

Farrall, Martin ;

Duga, Stefano ;

Merlini, Pier Angelica ;

Asselta, Rosanna ;

Girelli, Domenico ;

Olivieri, Oliviero ;

Martinelli, Nicola ;

Yin, Wu ;

Reilly, Dermot ;

Speliotes, Elizabeth ;

Fox, Caroline S. ;

Hveem, Kristian ;

Holmen, Oddgeir L. ;

Nikpay, Majid ;

Farlow, Deborah N. ;

Assimes, Themistocles L. ;

Franceschini, Nora ;

Robinson, Jennifer ;

North, Kari E. ;

Martin, Lisa W. ;

DePristo, Mark ;

Gupta, Namrata ;

Escher, Stefan A. ;

Jansson, Jan-Hakan ;

Van Zuydam, Natalie ;

Palmer, Colin N. A. ;

Wareham, Nicholas ;

Koch, Werner ;

Meitinger, Thomas ;

Peters, Annette ;

Lieb, Wolfgang .

NEW ENGLAND JOURNAL OF MEDICINE, 2014, 371 (01) :22-31

[10]

Di Angelantonio E, 2009, JAMA-J AM MED ASSOC, V302, P1993, DOI 10.1001/jama.2009.1619

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