Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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


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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Effect of a SNP on the levels of triglycerides and LDL-C and on risk for CAD.

Similar content being viewed by others


  1. Murray, C.J. & Lopez, A.D. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet 349, 1436–1442 (1997).

    Article  CAS  Google Scholar 

  2. Di Angelantonio, E. et al. Major lipids, apolipoproteins, and risk of vascular disease. J. Am. Med. Assoc. 302, 1993–2000 (2009).

    Article  CAS  Google Scholar 

  3. Sarwar, N. et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation 115, 450–458 (2007).

    Article  CAS  Google Scholar 

  4. Sheehan, N.A., Didelez, V., Burton, P.R. & Tobin, M.D. Mendelian randomisation and causal inference in observational epidemiology. PLoS Med. 5, e177 (2008).

    Article  Google Scholar 

  5. Smith, G.D. & Ebrahim, S. 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? Int. J. Epidemiol. 32, 1–22 (2003).

    Article  Google Scholar 

  6. Ebrahim, S. & Davey Smith, G. Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology? Hum. Genet. 123, 15–33 (2008).

    Article  Google Scholar 

  7. Smith, G.D. et al. Clustered environments and randomized genes: a fundamental distinction between conventional and genetic epidemiology. PLoS Med. 4, e352 (2007).

    Article  Google Scholar 

  8. Smith, G.D. & Ebrahim, S. Mendelian randomization: prospects, potentials, and limitations. Int. J. Epidemiol. 33, 30–42 (2004).

    Article  Google Scholar 

  9. Cohen, J.C., Boerwinkle, E., Mosley, T.H. Jr. & Hobbs, H.H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354, 1264–1272 (2006).

    Article  CAS  Google Scholar 

  10. Willer, C.J. et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat. Genet. 40, 161–169 (2008).

    Article  CAS  Google Scholar 

  11. Voight, B.F. et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 380, 572–580 (2012).

    Article  CAS  Google Scholar 

  12. Haase, C.L. et al. LCAT, HDL cholesterol and ischemic cardiovascular disease: a Mendelian randomization study of HDL cholesterol in 54,500 individuals. J. Clin. Endocrinol. Metab. 97, E248–E256 (2012).

    Article  CAS  Google Scholar 

  13. Haase, C.L., Tybjaerg-Hansen, A., Grande, P. & Frikke-Schmidt, R. Genetically elevated apolipoprotein A-I, high-density lipoprotein cholesterol levels, and risk of ischemic heart disease. J. Clin. Endocrinol. Metab. 95, E500–E510 (2010).

    Article  CAS  Google Scholar 

  14. Frikke-Schmidt, R. et al. Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease. J. Am. Med. Assoc. 299, 2524–2532 (2008).

    Article  CAS  Google Scholar 

  15. Johannsen, T.H. et al. Hepatic lipase, genetically elevated high-density lipoprotein, and risk of ischemic cardiovascular disease. J. Clin. Endocrinol. Metab. 94, 1264–1273 (2009).

    Article  CAS  Google Scholar 

  16. Kathiresan, S. et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat. Genet. 41, 56–65 (2009).

    Article  CAS  Google Scholar 

  17. Teslovich, T.M. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010).

    Article  CAS  Google Scholar 

  18. Sarwar, N. et al. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet 375, 1634–1639 (2010).

    Article  CAS  Google Scholar 

  19. Lewis, S.J. Mendelian randomization as applied to coronary heart disease, including recent advances incorporating new technology. Circ Cardiovasc Genet 3, 109–117 (2010).

    Article  Google Scholar 

  20. Global Lipids Genetics Consortium. Discovery and refinement of loci associated with lipid levels. Nat. Genet. 10.1038/ng.2797 (6 October 2013).

  21. Schunkert, H. et al. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat. Genet. 43, 333–338 (2011).

    Article  CAS  Google Scholar 

  22. Pennacchio, L.A. et al. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science 294, 169–173 (2001).

    Article  CAS  Google Scholar 

  23. Kathiresan, S. et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat. Genet. 40, 189–197 (2008).

    Article  CAS  Google Scholar 

  24. Pollin, T.I. et al. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science 322, 1702–1705 (2008).

    Article  CAS  Google Scholar 

  25. Deloukas, P. et al. Large-scale association analysis identifies new risk loci for coronary artery disease. Nat. Genet. 45, 25–33 (2013).

    Article  CAS  Google Scholar 

  26. Miller, M. et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 123, 2292–2333 (2011).

    Article  Google Scholar 

  27. Varbo, A. et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J. Am. Coll. Cardiol. 61, 427–436 (2013).

    Article  CAS  Google Scholar 

  28. Wilson, P.W. et al. Prediction of coronary heart disease using risk factor categories. Circulation 97, 1837–1847 (1998).

    Article  CAS  Google Scholar 

  29. Bosch, J. et al. n–3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N. Engl. J. Med. 367, 309–318 (2012).

    Article  CAS  Google Scholar 

  30. Rubins, H.B. et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N. Engl. J. Med. 341, 410–418 (1999).

    Article  CAS  Google Scholar 

  31. Keech, A. et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366, 1849–1861 (2005).

    Article  CAS  Google Scholar 

  32. Ginsberg, H.N. et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N. Engl. J. Med. 362, 1563–1574 (2010).

    Article  Google Scholar 

  33. 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

  34. Cook, R.D. Detection of influential observations in linear regression. Technometrics 19, 15–18 (1977).

    Google Scholar 

Download references


We thank the Global Lipids Genetics Consortium for early access to the association results of the Metabochip study. S. Kathiresan is supported by a Research Scholar award from the Massachusetts General Hospital, the Howard Goodman Fellowship from Massachusetts General Hospital, the Donovan Family Foundation, R01HL107816 from the US National Institutes of Health and a grant from Fondation Leducq. R.D. is supported by a Banting Fellowship from the Canadian Institutes of Health Research. G.P. is supported by award T32HL007208 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the US National Institutes of Health.

Author information

Authors and Affiliations



R.D. carried out primary data analyses and prepared the supplementary information. R.D. and C. Gao prepared figures and tables. C.J.W., E.M.S., S. Sengupta, S.S.R. and G.R.A. contributed meta-analysis results. J.C. and M.L.B. performed bioinformatic analyses. R.D., M.J.D., B.M.N. and S. Kathiresan contributed to the design and conduct of the study. R.D., M.J.D., B.M.N. and S. Kathiresan wrote the manuscript.

All authors contributed to the research and reviewed the manuscript.

Design, management and coordination of contributing cohorts: (ADVANCE) T.L.A.; (AGES Reykjavik study) T.B.H. and V.G.; (AIDHS/SDS) D.K.S.; (AMC-PAS) P.D. and G.K.H.; (Amish GLGC) A.R.S.; (ARIC) E.B.; (B58C-WTCCC and B58C-T1DGC) D.P.S.; (B58C-Metabochip) C.M.L., C. Power and M.I.M.; (BLSA) L.F.; (BRIGHT) P.B.M.; (CARDIoGRAM) N.S.; (CHS) B.M.P. and J.I.R.; (CLHNS) A.B.F., K.L.M. and L.S.A.; (CoLaus) P.V.; (CROATIA-Vis) C.H. and I.R.; (deCODE) K. Stefansson and U.T.; (DIAGEN) P.E.H.S. and S.R.B.; (DILGOM) S.R.; (DPS) M.U.; (DR's EXTRA) R.R.; (EAS) J.F.P.; (EGCUT (Estonian Genome Center of the University of Tartu)) A.M.; (ELY) N.J.W.; (ENGAGE) N.B.F.; (EPIC) N.W. and K.-T.K.; (EPIC_N_OBSET GWAS) E.H.Y.; (ERF) C.M.v.D.; (ESS (Erasmus Stroke Study)) P.J.K.; (Family Heart Study (FHS)) I.B.B.; (FBPP) A.C., R.S.C. and S.C.H.; (FENLAND) R.J.F.L. and N.W.; (FIN-D2D 2007) A.K. and L.M.; (FINCAVAS) M. Kähönen; (Framingham) L.A.C., S. Kathiresan and J.M.O.; (FRISCII) A. Siegbahn and L.W.; (FUSION GWAS) K.L.M. and M. Boehnke; (FUSION stage 2) F.S.C., J.T. and J. Saramies; (GenomEUTwin) J.B.W., N.G.M., K.O.K., V.S., J. Kaprio, A. Jula, D.I.B., N.L.P. and T.D.S.; (GLACIER) P.W.F. and G.H.; (Go-DARTS) A.D.M. and C.N.A.P.; (GxE/Spanish Town) B.O.T., C.A.M., F.B., J.N.H. and R.S.C.; (HUNT2) K. Hveem; (IMPROVE) U.d.F., A. Hamsten, E.T. and S.E.H.; (InCHIANTI) S.B.; (KORAF4) C. Gieger; (LifeLines) B.H.R.W.; (LOLIPOP) J.S.K. and J.C.C.; (LURIC) B.O.B. and W.M.; (MDC) L.C.G., D. Altshuler and S. Kathiresan; (MEDSTAR) M.S.B. and S.E.E.; (METSIM) J. Kuusisto and M.L.; (MICROS) P.P.P.; (MORGAM) D. Arveiler and J.F.; (MRC/UVRI GPC GWAS) P. Kaleebu, G.A., J. Seeley and E.H.Y.; (MRC National Survey of Health and Development) D.K.; (NFBC1986) M.-R.J.; (NSPHS) U.G.; (ORCADES) H.C.; (PARC) Y.-D.I.C., R.M.K. and J.I.R.; (PennCath) D.J.R. and M.P.R.; (PIVUS) E.I. and L.L.; (PROMIS) J.D., P.D. and D. Saleheen; (Rotterdam Study) A. Hofman and A.G.U.; (SardiNIA) G.R.A.; (SCARFSHEEP) A. Hamsten and U.d.F.; (SEYCHELLES) M. Burnier, M. Bochud and P. Bovet; (SUVIMAX) P.M.; (Swedish Twin Registry) E.I. and N.L.P.; (TAICHI) T.L.A., Y.-D.I.C., C.A.H., T.Q., J.I.R. and W.H.-H.S.; (THISEAS) G.D. and P.D.; (Tromsø) I.N.; (TWINGENE) U.d.F. and E.I.; (ULSAM) E.I.; and (Whitehall II) A. Hingorani and M. Kivimaki.

Genotyping of contributing cohorts: (ADVANCE) D. Absher; (AIDHS/SDS) L.F.B. and M.L.G.; (AMC-PAS) P.D. and G.K.H.; (B58C-WTCCC and B58C-T1DGC) W.L.M.; (B58C-Metabochip) M.I.M.; (BLSA) D.H.; (BRIGHT) P.B.M.; (CHS) J.I.R.; (DIAGEN) N.N. and G.M.; (DILGOM) A. Palotie; (DR's EXTRA) T.A.L.; (EAS) J.F.W.; (EGCUT (Estonian Genome Center of the University of Tartu)) T.E.; (EPIC) P.D.; (EPIC_N_SUBCOH GWAS) I.B.; (ERF) C.M.v.D.; (ESS (Erasmus Stroke Study)) C.M.v.D.; (FBPP) A.C. and G.B.E.; (FENLAND) M.S.S.; (FIN-D2D 2007) A.J.S.; (FINCAVAS) T.L.; (Framingham) J.M.O.; (FUSION stage 2) L.L.B.; (GLACIER) I.B.; (Go-DARTS) C.J.G., C.N.A.P. and M.I.M.; (IMPROVE) A. Hamsten; (KORAF3) H.G. and T.I.; (KORAF4) N.K.; (LifeLines) C.W.; (LOLIPOP) J.S.K. and J.C.C.; (LURIC) M.E.K.; (MDC) B.F.V. and R.D.; (MICROS) A.A.H.; (MORGAM) L.T. and P. Brambilla; (MRC/UVRI GPC GWAS) M.S.S.; (MRC National Survey of Health and Development) A.W., D.K. and K.K.O.; (NFBC1986) A.-L.H., M.-R.J., M.I.M., P.E. and S.V.; (NSPHS and FRISCII) Å. Johansson; (ORCADES) H.C.; (PARC) M.O.G., M.R.J. and J.I.R.; (PIVUS) E.I. and L.L.; (PROMIS) P.D. and K. Stirrups; (Rotterdam Study) A.G.U. and F.R.; (SardiNIA) R.N.; (SCARFSHEEP) B.G. and R.J.S.; (SEYCHELLES) F.M. and G.B.E.; (Swedish Twin Registry) E.I. and N.L.P.; (TAICHI) D. Absher, T.L.A., E.K., T.Q. and L.L.W.; (THISEAS) P.D.; (TWINGENE) A. Hamsten and E.I.; (ULSAM) E.I.; (WGHS) S.M., D.I.C. and P.M.R.; and (Whitehall II) A. Hingorani, C.L., M. Kumari and M. Kivimaki.

Phenotype definition of contributing cohorts: (ADVANCE) C.I.; (AGES Reykjavik study) T.B.H. and V.G.; (AIDHS/SDS) L.F.B.; (AMC-PAS) J.J.P.K.; (Amish GLGC) A.R.S. and B.D.M.; (B58C-WTCCC and B58C-T1DGC) D.P.S.; (B58C-Metabochip) C. Power and E.H.; (BRIGHT) P.B.M.; (CHS) B.M.P.; (CoLaus) P.V.; (deCODE) G.I.E., H.H. and I.O.; (DIAGEN) G.M.; (DILGOM) K. Silander; (DPS) J. Lindström; (DR's EXTRA) P. Komulainen; (EAS) J.L.B.; (EGCUT (Estonian Genome Center of the University of Tartu)) A.M.; (EGCUT (Estonian Genome Center of the University of Tartu)) K.F.; (ERF and Rotterdam Study) A. Hofman; (ERF) C.M.v.D.; (ESS (Erasmus Stroke Study)) E.G.V.d.H., H.M.D.H. and P.J.K.; (FBPP) A.C., R.S.C. and S.C.H.; (FINCAVAS) T.V.M.N.; (Framingham) S. Kathiresan and J.M.O.; (GenomEUTwin: MZGWA) J.B.W.; (GenomEUTwin-FINRISK) V.S.; (GenomEUTwin-FINTWIN) J. Kaprio and K. Heikkilä; (GenomEUTwin-GENMETS) A. Jula; (GenomEUTwin-NLDTWIN) G.W.; (Go-DARTS) A.S.F.D., A.D.M., C.N.A.P. and L.A.D.; (GxE/Spanish Town) C.A.M. and F.B.; (IMPROVE) U.d.F., A. Hamsten and E.T.; (KORAF3) C.M.; (KORAF4) A. Döring; (LifeLines) L.J.v.P.; (LOLIPOP) J.S.K. and J.C.C.; (LURIC) H.S.; (MDC) L.C.G.; (METSIM) A. Stančáková; (MORGAM) G.C.; (MRC/UVRI GPC GWAS) R.N.N.; (MRC National Survey of Health and Development) D.K.; (NFBC1986) A.R., A.-L.H., A. Pouta and M.-R.J.; (NSPHS and FRISCII) Å. Johansson; (NSPHS) U.G.; (ORCADES) S.H.W.; (PARC) Y.-D.I.C. and R.M.K.; (PIVUS) E.I. and L.L.; (PROMIS) D.F.F.; (Rotterdam Study) A. Hofman; (SCARFSHEEP) U.d.F. and B.G.; (SEYCHELLES) M. Burnier, M. Bochud and P. Bovet; (Swedish Twin Registry) E.I. and N.L.P.; (TAICHI) H.-Y.C., C.A.H., Y.-J.H., E.K., S.-Y.L. and W.H.-H.S.; (THISEAS) G.D. and M.D.; (Tromsø) T.W.; (TWINGENE) U.d.F. and E.I.; (ULSAM) E.I.; (WGHS) P.M.R.; and (Whitehall II) M. Kumari.

Primary analysis from contributing cohorts: (ADVANCE) L.L.W.; (AIDHS/SDS) R.S.; (AMC-PAS) S. Kanoni; (Amish GLGC) J.R.O. and M.E.M.; (ARIC) K.A.V.; (B58C-Metabochip) C.M.L., E.H. and T.F.; (B58C-WTCCC and B58C-T1DGC) D.P.S.; (BLSA) T.T.; (BRIGHT) T.J.; (CLHNS) Y.W.; (CoLaus) J.S.B.; (deCODE) G.T.; (DIAGEN) A.U.J.; (DILGOM) M.P.; (EAS) R.M.F.; (DPS) A.U.J.; (DR'S EXTRA) A.U.J.; (EGCUT (Estonian Genome Center of the University of Tartu)) E.M., K.F. and T.E.; (ELY) D.G.; (EPIC) K. Stirrups and D.G.; (EPIC_N_OBSET GWAS) E.H.Y. and C.L.; (EPIC_N_SUBCOH GWAS) N.W.; (ERF) A.I.; (ESS (Erasmus Stroke Study)) C.M.v.D. and E.G.V.d.H.; (EUROSPAN) A. Demirkan; (Family Heart Study (FHS)) I.B.B. and M.F.F.; (FBPP) A.C. and G.B.E.; (FENLAND) T.P. and C. Pomilla; (FENLAND GWAS) J.H.Z. and J. Luan; (FIN-D2D 2007) A.U.J.; (FINCAVAS) L.-P.L.; (Framingham) L.A.C. and G.M.P.; (FRISCII and NSPHS) Å. Johansson; (FUSION stage 2) T.M.T.; (GenomEUTwin-FINRISK) J. Kettunen; (GenomEUTwin-FINTWIN) K. Heikkilä; (GenomEUTwin-GENMETS) I.S.; (GenomEUTwin-SWETWIN) P.K.E.M.; (GenomEUTwin-UK-TWINS) M.M.; (GLACIER) D. Shungin; (GLACIER) P.W.F.; (Go-DARTS) C.N.A.P. and L.A.D.; (GxE/Spanish Town) C.D.P.; (HUNT) A.U.J.; (IMPROVE) R.J.S.; (InCHIANTI) T.T.; (KORAF3) M.M.-N.; (KORAF4) A.-K.P.; (LifeLines) I.M.N.; (LOLIPOP) W.Z.; (LURIC) M.E.K.; (MDC) B.F.V.; (MDC) P.F. and R.D.; (METSIM) A.U.J.; (MRC/UVRI GPC GWAS) R.N.N.; (MRC National Survey of Health and Development) A.W. and J. Luan; (NFBC1986) M. Kaakinen, I.S. and S.K.S.; (NSPHS and FRISCII) Å. Johansson; (PARC) X.L.; (PIVUS) C. Song and E.I.; (PROMIS) J.D., D.F.F. and K. Stirrups; (Rotterdam Study) A.I.; (SardiNIA) C. Sidore, J.L.B.-G. and S. Sanna; (SCARFSHEEP) R.J.S.; (SEYCHELLES) G.B.E. and M. Bochud; (SUVIMAX) T.J.; (Swedish Twin Registry) C. Song and E.I.; (TAICHI) D. Absher, T.L.A., H.-Y.C., M.O.G., C.A.H., T.Q. and L.L.W.; (THISEAS) S. Kanoni; (Tromsø) A.U.J.; (TWINGENE) A.G. and E.I.; (ULSAM) C. Song, E.I. and S.G.; (WGHS) D.I.C.; and (Whitehall II) S. Shah.

Corresponding authors

Correspondence to Mark J Daly, Benjamin M Neale or Sekar Kathiresan.

Ethics declarations

Competing interests

B.M.P. serves on the Data and Safety Monitoring Board of a clinical trial funded by the manufacturer (Zoll), and he serves on the Steering Committee of the Yale Open-Data Project funded by the Medtronic. P.V. received an unrestricted grant from GlaxoSmithKline to build the CoLaus study. G.T., H.H., A.K., K. Stefansson and U.T. are employees of deCODE Genetics/Amgen, a biotechnology company. I.B. and spouse own stock in GlaxoSmithKline and Incyte, Ltd. S. Kathiresan serves on scientific advisory boards for Merck, Celera, American Genomics and Catabasis. He has received unrestricted research grants from Merck and Pfizer.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1–4 and Supplementary Tables 1–10 (PDF 1720 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Do, R., Willer, C., Schmidt, E. et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet 45, 1345–1352 (2013).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links