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

Author
item DO, RON - Massachusetts General Hospital
item WILLER, CRISTEN - University Of Michigan
item SCHMIDT, ELLEN - University Of Michigan
item SENGUPTA, SEBANTI - University Of Michigan
item GAO, CHI - Massachusetts General Hospital
item PELOSO, GINA - Massachusetts General Hospital
item GUSTAFSSON, STEGAN - Uppsala University
item KANONI, STAVROULA - Wellcome Trust Sanger Institute
item GANNA, ANDREA - Uppsala University
item CHEN, JIN - University Of Michigan
item BUCHKOVICH, MARTIN - University Of North Carolina
item MORA, SAMIA - Brigham & Women'S Hospital
item BECKMANN, JACQUES - Lausanne University Hospital
item BRAGG-GRESHAM, JENNIFER - University Of Michigan
item CHANG, HSING-YI - Institute Of Population Health Sciences
item DEMIRKAN, AYSE - Erasmus Medical Center
item DEN HERTOG, HELEEN - Erasmus Medical Center
item DONNELLY, LOUISE - University Of Dundee
item EHRET, GEORG - Geneva University Hospital
item ESKO, TONU - Broad Institute Of Mit/harvard
item FEITOSA, MARY - Washington University
item FERREIRA, TERESA - University Of Oxford
item FISCHER, KRISTA - University Of Tartu
item FONTANILLAS, PIERRE - Broad Institute Of Mit/harvard
item FRASER, ROSS - University Of Edinburgh
item FREITAG, DANIEL - University Of Cambridge
item GURDASANI, DEEPTI - Wellcome Trust Sanger Institute
item HEIKKILÄ, KAUKO - University Of Helsinki
item HYPPÖNEN, ELINA - University College London
item ISAACS, AARON - Erasmus Medical Center
item JACKSON, ANNE - University Of Michigan
item JOHANSSON, ASA - Uppsala University
item JOHNSON, TOBY - Queen Mary University Of London
item KAAKINEN, MARIKA - University Of Oulu
item KETTUNEN, JOHANNES - University Of Helsinki
item KLEBER, MARCUS - University Of Ulm Medical Center
item LI, XIAOHUI - Cedars-Sinai Medical Center
item LUAN, JIAN'AN - Addenbrooke'S Hospital
item LYYTIKÄINEN, LEO-PEKKA - Fimlab Laboratories
item MAGNUSSON, PATRIK K E - Karolinska Institute
item MANGINO, MASSIMO - King'S College
item MIHAILOV, EVELIN - University Of Tartu
item MONTASSER, MARY - University Of Maryland
item MÜLLER-NURASYID, MARTINA - Ludwig-Maximilians University
item NOLTE, LLJM - University Of Groningen
item O'CONNELL, JEFFREY - University Of Maryland
item PALMER, CAMERON - Broad Institute Of Mit/harvard
item PEROLA, MARKUS - University Of Tartu
item PETERSEN, ANN-KRISTIN - German Research Center For Environmental Health
item SANNA, SERENA - Instituto Di Ricerca Genetica E Biomedica
item SAXENA, RICHA - Massachusetts General Hospital
item SERVICE, SUSAN - Ucla Health System
item SHAH, SONIA - University College London
item SHUNGIN, DMITRY - Scania University Hospital
item SIDORE, CARLO - University Of Michigan
item SONG, CI - Uppsala University
item STRAWBRIDGE, RONA - Karolinska University Hospital
item SURAKKA, IDA - University Of Helsinki
item TANAKA, TOSHIKO - National Institutes Of Health (NIH)
item TESLOVICH, TANYA - University Of Michigan
item THORLEIFSSON, GUDMAR - Amgen, Inc
item VAN DEN HERIK, EVITA - Erasmus Medical Center
item VOIGHT, BENJAMIN - University Of Pennsylvania
item VOLCIK, KELLY - University Of Texas Health Science Center
item WAITE, LINDSAY - Hudsonalpha Institute For Biotechnology
item WONG, ANDREW - University College London
item WU, YING - University Of North Carolina
item ZHANG, WEIHUA - Imperial College
item ABSHER, DEVIN - Hudsonalpha Institute For Biotechnology
item ASIKI, GERSHIM - Uganda Virus Research Institute
item BARROSO, INES - Wellcome Trust Sanger Institute
item BEEN, LATONYA - University Of Oklahoma
item BOLTON, JENNIFER - University Of Edinburgh
item BONNYCASTLE, LORI - National Institutes Of Health (NIH)
item BRAMBILLA, PAOLO - University Of Milano
item BURNETT, MARY - Medstar Research Institute
item CESANA, GIANCARLO - University Of Milano
item DIMITRIOUS, MARIA - Harokopio University Of Athens
item DONEY, ALEX S - University Of Dundee
item DORING, ANGELA - German Research Center For Environmental Health
item ELLIOTT, PAUL - University Of Oulu
item EPSTEIN, STEPHEN - Medstar Research Institute
item EYJOLFSSON, GUDMUNDUR INGI - Icelandic Medical Center
item GIGANTE, BRUNA - Karolinska Institute
item GOODARZI, MARK - Cedars-Sinai Medical Center
item GRALLERT, HARALD - Helmholtz Centre
item GRAVITO, MARTHA - University Of Oklahoma
item GROVES, CHRISTPHER - University Of Oxford
item HALLMANS, GORAN - University Of Umea
item HARTIKAINEN, ANNA LIISA - University Of Oulu
item HAYWARD, CAROLINE - Western General Hospital
item HERNANDEZ, DENA - National Institute On Aging (NIA, NIH)
item HICKS, ANDREW - Institute Of Population Health Sciences
item HOLM, HILMA - Amgen, Inc
item HUNG, YI-JEN - Tri-Service General Hospital
item ILLIG, THOMAS - Helmholtz Centre
item JONES, MICHELLE - Cedars-Sinai Medical Center
item KALEEBU, PONTINAO - Uganda Virus Research Institute
item ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Nature Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/13/2013
Publication Date: 10/6/2013
Citation: Do, R., Willer, C.J., Schmidt, E.M., Sengupta, S., Gao, C., Peloso, G.M., Gustafsson, S., Kanoni, S., Ganna, A., Chen, J., Buchkovich, M.L., Mora, S., Beckmann, J.S., Bragg-Gresham, J.L., Chang, H., Demirkan, A., Den Hertog, H.M., Donnelly, L.A., Ehret, G.B., Esko, T., Feitosa, M.F., Ferreira, T., Fischer, K., Fontanillas, P., Fraser, R.M., Freitag, D.F., Gurdasani, D., Heikkilä, K., Hyppönen, E., Isaacs, A. 2013. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nature Genetics. 45(11):1345-1352. DOI: 10.1038/NG.2795.

Interpretive Summary: Triglycerides are transported in blood 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 is causative or the result of the correlation of triglyceride levels with other CAD risk factors. In order to answer this question, we used 185 common genetic variants recently identified for blood lipids to examine the direct role of triglycerides in risk for CAD. First, we focused on genes associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we showed that they both are positively associated with CAD risk. Second, we considered genes exclusively associated with triglycerides and showed that these genes were also associated with CAD. Finally, when we accounted 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 support that triglyceride-rich lipoproteins causally influence risk for CAD. Therefore, they should be considered as primary targets for CAD risk modification and disease prevention.

Technical Abstract: 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 × 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.