Common variants associated with plasma triglycerides and risk for coronary artery disease

被引：723

作者：

Do, Ron

Willer, Cristen J.

Schmidt, Ellen M.

Sengupta, Sebanti

Gao, Chi

Peloso, Gina M.

Gustafsson, Stefan

Kanoni, Stavroula

Ganna, Andrea

Chen, Jin

Buchkovich, Martin L.

Mora, Samia

Beckmann, Jacques S.

Bragg-Gresham, Jennifer L.

Chang, Hsing-Yi

Demirkan, Ayse

Den Hertog, Heleen M. ^{[1
]}

Donnelly, Louise A. ^{[2
,3
]}

Ehret, Georg B. ^{[4
,5
]}

Esko, Tonu ^{[6
,7
]}

Feitosa, Mary F. ^{[8
]}

Ferreira, Teresa ^{[9
]}

Fischer, Krista ^{[6
]}

Fontanillas, Pierre

Fraser, Ross M. ^{[10
]}

Freitag, Daniel F. ^{[11
]}

Gurdasani, Deepti ^{[11
]}

Heikkila, Kauko ^{[12
]}

Hyppoenen, Elina ^{[13
]}

Isaacs, Aaron ^{[14
]}

Jackson, Anne U.

Johansson, Asa ^{[15
,16
]}

Johnson, Toby ^{[17
,18
]}

Kaakinen, Marika ^{[19
,20
]}

Kettunen, Johannes ^{[21
,22
]}

Kleber, Marcus E. ^{[23
,24
]}

Li, Xiaohui ^{[25
]}

Luan, Jian'an ^{[26
]}

Lyytikainen, Leo-Pekka ^{[27
,28
]}

Magnusson, Patrik K. E.

Mangino, Massimo ^{[29
]}

Mihailov, Evelin ^{[6
,7
]}

Montasser, May E. ^{[30
]}

Mueller-Nurasyid, Martina ^{[31
,32
,33
]}

Nolte, Ilja M. ^{[34
]}

O'Connell, Jeffrey R. ^{[30
]}

Palmer, Cameron D. ^{[35
,36
]}

Perola, Markus ^{[6
,21
,22
]}

Petersen, Ann-Kristin ^{[31
]}

Sanna, Serena ^{[37
]}

机构：

[1] Erasmus MC, Dept Neurol, Rotterdam, Netherlands

[2] Univ Dundee, Ninewells Hosp, Med Res Inst, Dundee, Scotland

[3] Sch Med, Dundee, Scotland

[4] Univ Hosp Geneva, Dept Special Med, Geneva, Switzerland

[5] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA

[6] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia

[7] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia

[8] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA

[9] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[10] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland

[11] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England

[12] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland

[13] UCL, Inst Child Hlth, MRC, Ctr Paediat Epidemiol & Biostat,Ctr Epidemiol Chi, London, England

[14] Ctr Med Syst Biol, Leiden, Netherlands

[15] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden

[16] Uppsala Univ, Uppsala Clin Res Ctr, Uppsala, Sweden

[17] Queen Mary Univ London, Barts & London Sch Med & Dent, Genome Ctr, London, England

[18] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst,Natl Inst Hlth Res, Cardiovasc Biomed Res Unit, London, England

[19] Univ Oulu, Bioctr Oulu, Oulu, Finland

[20] Univ Oulu, Inst Hlth Sci, Oulu, Finland

[21] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland

[22] Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland

[23] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89069 Ulm, Germany

[24] Heidelberg Univ, Med Fac Mannheim, Mannheim Inst Publ Hlth Social & Prevent Med, Mannheim, Germany

[25] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA

[26] Addenbrookes Hosp, Inst Metab Sci, Epidemiol Unit, MRC, Cambridge, England

[27] Tampere Univ Hosp, Dept Clin Chem, Fimlab Labs, FIN-33521 Tampere, Finland

[28] Univ Tampere, Sch Med, Dept Clin Chem, FIN-33101 Tampere, Finland

[29] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England

[30] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA

[31] Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany

[32] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany

[33] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany

[34] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands

[35] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA

[36] Childrens Hosp, Div Genet, Program Genom, Boston, MA 02115 USA

[37] CNR, Ist Ric Genet & Biomed, Monserrato, Italy

[38] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Ctr Neurobehav Genet, Los Angeles, CA 90024 USA

[39] UCL, Dept Epidemiol & Publ Hlth, Genet Epidemiol Grp, London, England

[40] Lund Univ, Ctr Diabet, Scania Univ Hosp, Dept Clin Sci,Genet & Mol Epidemiol Unit, Malmo, Sweden

[41] Umea Univ, Dept Odontol, Umea, Sweden

[42] Umea Univ, Dept Publ Hlth & Primary Care, Med Unit, Umea, Sweden

[43] Univ Sassari, Dipartimento Sci Biomed, I-07100 Sassari, Italy

[44] Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden

[45] Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden

[46] NIH, Clin Res Branch, Baltimore, MD USA

[47] deCODE Genet Amgen, Reykjavik, Iceland

[48] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA

[49] Univ Penn, Sch Med, Dept Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USA

[50] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA

来源：

NATURE GENETICS | 2013年 / 45卷 / 11期

基金：

美国国家卫生研究院; 加拿大健康研究院;

关键词：

HIGH-DENSITY-LIPOPROTEIN; MENDELIAN RANDOMIZATION; HEART-DISEASE; CARDIOVASCULAR-DISEASE; GENETIC EPIDEMIOLOGY; CHOLESTEROL LEVELS; LOCI; CONTRIBUTE; THERAPY;

D O I：

10.1038/ng.2795

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

引用

页码：1345 / +

页数：9

共 34 条

[1]

A map of human genome variation from population-scale sequencing [J].

Altshuler, David ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Collins, Francis S. ;

De la Vega, Francisco M. ;

Donnelly, Peter ;

Egholm, Michael ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Knoppers, Bartha M. ;

Lander, Eric S. ;

Lehrach, Hans ;

Mardis, Elaine R. ;

McVean, Gil A. ;

Nickerson, DebbieA. ;

Peltonen, Leena ;

Schafer, Alan J. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Deiros, David ;

Metzker, Mike ;

Muzny, Donna ;

Reid, Jeff ;

Wheeler, David ;

Wang, Jun ;

Li, Jingxiang ;

Jian, Min ;

Li, Guoqing ;

Li, Ruiqiang ;

Liang, Huiqing ;

Tian, Geng ;

Wang, Bo ;

Wang, Jian ;

Wang, Wei ;

Yang, Huanming ;

Zhang, Xiuqing ;

Zheng, Huisong ;

Lander, Eric S. ;

Altshuler, David L. ;

Ambrogio, Lauren ;

Bloom, Toby ;

Cibulskis, Kristian ;

Fennell, Tim J. ;

Gabriel, Stacey B. .

NATURE, 2010, 467 (7319) :1061-1073

[2]

n-3 Fatty Acids and Cardiovascular Outcomes in Patients with Dysglycemia [J].

Bosch, Jackie ;

Gerstein, Hertzel C. ;

Dagenais, Gilles R. ;

Diaz, Rafael ;

Dyal, Leanne ;

Jung, Hyejung ;

Maggiono, Aldo P. ;

Probstfield, Jeffrey ;

Ramachandran, Ambady ;

Riddle, Matthew C. ;

Ryden, Lars E. ;

Yusuf, Salim .

NEW ENGLAND JOURNAL OF MEDICINE, 2012, 367 (04) :309-318

[3]

Sequence variations in PCSK9, low LDL, and protection against coronary heart disease [J].

Cohen, JC ;

Boerwinkle, E ;

Mosley, TH ;

Hobbs, HH .

NEW ENGLAND JOURNAL OF MEDICINE, 2006, 354 (12) :1264-1272

[4]

DETECTION OF INFLUENTIAL OBSERVATION IN LINEAR-REGRESSION [J].

COOK, RD .

TECHNOMETRICS, 1977, 19 (01) :15-18

[5]

Large-scale association analysis identifies new risk loci for coronary artery disease [J].

Deloukas, Panos ;

Kanoni, Stavroula ;

Willenborg, Christina ;

Farrall, Martin ;

Assimes, Themistocles L. ;

Thompson, John R. ;

Ingelsson, Erik ;

Saleheen, Danish ;

Erdmann, Jeanette ;

Goldstein, Benjamin A. ;

Stirrups, Kathleen ;

Koenig, Inke R. ;

Cazier, Jean-Baptiste ;

Johansson, Asa ;

Hall, Alistair S. ;

Lee, Jong-Young ;

Willer, Cristen J. ;

Chambers, John C. ;

Esko, Tonu ;

Folkersen, Lasse ;

Goel, Anuj ;

Grundberg, Elin ;

Havulinna, Aki S. ;

Ho, Weang K. ;

Hopewell, Jemma C. ;

Eriksson, Niclas ;

Kleber, Marcus E. ;

Kristiansson, Kati ;

Lundmark, Per ;

Lyytikainen, Leo-Pekka ;

Rafelt, Suzanne ;

Shungin, Dmitry ;

Strawbridge, Rona J. ;

Thorleifsson, Gudmar ;

Tikkanen, Emmi ;

Van Zuydam, Natalie ;

Voight, Benjamin F. ;

Waite, Lindsay L. ;

Zhang, Weihua ;

Ziegler, Andreas ;

Absher, Devin ;

Altshuler, David ;

Balmforth, Anthony J. ;

Barroso, Ines ;

Braund, Peter S. ;

Burgdorf, Christof ;

Claudi-Boehm, Simone ;

Cox, David ;

Dimitriou, Maria ;

Do, Ron .

NATURE GENETICS, 2013, 45 (01) :25-U52

[6]

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

[7]

Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology? [J].

Ebrahim, Shah ;

Smith, George Davey .

HUMAN GENETICS, 2008, 123 (01) :15-33

[8]

Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease [J].

Frikke-Schmidt, Ruth ;

Nordestgaard, Borge G. ;

Stene, Maria C. A. ;

Sethi, Amar A. ;

Remaley, Alan T. ;

Schnohr, Peter ;

Grande, Peer ;

Tybjaerg-Hansen, Anne .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2008, 299 (21) :2524-2532

[9]

Ginsberg HN, 2010, NEW ENGL J MED, V362, P1563, DOI 10.1056/NEJMoa1001282

[10]

LCAT, HDL Cholesterol and Ischemic Cardiovascular Disease: A Mendelian Randomization Study of HDL Cholesterol in 54,500 Individuals [J].

Haase, Christiane L. ;

Tybjaerg-Hansen, Anne ;

Qayyum, Abbas Ali ;

Schou, Jesper ;

Nordestgaard, Borge G. ;

Frikke-Schmidt, Ruth .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2012, 97 (02) :E248-E256

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