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

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.

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

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Acknowledgements

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.

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Authors and Affiliations

Authors

Contributions

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.

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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.

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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). https://doi.org/10.1038/ng.2795

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