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.

Citing Articles

Beyond platelet activation: dysregulated lipid metabolism in defining risk and pathophysiology of VITT.

Stevens H, McFadyen J, Mellett N, Lynn D, Duong T, Giles C Res Pract Thromb Haemost. 2025; 9(1):102677.

PMID: 40041449 PMC: 11879676. DOI: 10.1016/j.rpth.2025.102677.

Ultra-small phospholipid nanoparticles in the treatment of combined hyperlipidemia: a randomized placebo-controlled clinical trial.

Archakov A, Kukharchuk V, Lisitsa A, Ponomarenko E, Romashova Y, Pleshakova T Res Pharm Sci. 2025; 19(6):656-668.

PMID: 39911895 PMC: 11792717. DOI: 10.4103/RPS.RPS_274_23.

Cardiovascular Diseases Among Indian Older Adults: A Comprehensive Review.

Jan B, Dar M, Choudhary B, Basist P, Khan R, Alhalmi A Cardiovasc Ther. 2025; 2024:6894693.

PMID: 39742010 PMC: 11323990. DOI: 10.1155/2024/6894693.

Renal Angptl4 is a key fibrogenic molecule in progressive diabetic kidney disease.

Srivastava S, Zhou H, Shenoi R, Morris M, Lainez-Mas B, Goedeke L Sci Adv. 2024; 10(49):eadn6068.

PMID: 39630889 PMC: 11616692. DOI: 10.1126/sciadv.adn6068.

Temporal changes in lipid concentrations and the prevalence of dyslipidemia among individuals with diabetes, prediabetes, and normal blood glucose from 2011 to 2015.

Zhao M, Cheng Y, Li M, Zhang W, Ji J, Lu F Lipids Health Dis. 2024; 23(1):394.

PMID: 39605064 PMC: 11603987. DOI: 10.1186/s12944-024-02375-8.

References

Davey Smith G, Ebrahim S . Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol. 2004; 33(1):30-42. DOI: 10.1093/ije/dyh132. View

Pollin T, Damcott C, Shen H, Ott S, Shelton J, Horenstein R . A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science. 2008; 322(5908):1702-5. PMC: 2673993. DOI: 10.1126/science.1161524. View

Cohen J, Boerwinkle E, Mosley Jr T, Hobbs H . Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006; 354(12):1264-72. DOI: 10.1056/NEJMoa054013. View

Ginsberg H, Elam M, Lovato L, Crouse 3rd J, Leiter L, Linz P . Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010; 362(17):1563-74. PMC: 2879499. DOI: 10.1056/NEJMoa1001282. View

Kathiresan S, Willer C, Peloso G, Demissie S, Musunuru K, Schadt E . Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 2008; 41(1):56-65. PMC: 2881676. DOI: 10.1038/ng.291. View

Rubins H, Robins S, Collins D, Fye C, Anderson J, Elam M . 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. 1999; 341(6):410-8. DOI: 10.1056/NEJM199908053410604. View

Murray C, Lopez A . Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet. 1997; 349(9063):1436-42. DOI: 10.1016/S0140-6736(96)07495-8. View

Miller M, Stone N, Ballantyne C, Bittner V, Criqui M, Ginsberg H . Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011; 123(20):2292-333. DOI: 10.1161/CIR.0b013e3182160726. View

Varbo A, Benn M, Tybjaerg-Hansen A, Jorgensen A, Frikke-Schmidt R, Nordestgaard B . Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol. 2012; 61(4):427-436. DOI: 10.1016/j.jacc.2012.08.1026. View

10.

Davey Smith G, Lawlor D, Harbord R, Timpson N, Day I, Ebrahim S . Clustered environments and randomized genes: a fundamental distinction between conventional and genetic epidemiology. PLoS Med. 2007; 4(12):e352. PMC: 2121108. DOI: 10.1371/journal.pmed.0040352. View

11.

Ebrahim S, Davey Smith G . Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology?. Hum Genet. 2007; 123(1):15-33. DOI: 10.1007/s00439-007-0448-6. View

12.

Kathiresan S, Melander O, Guiducci C, Surti A, Burtt N, Rieder M . Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet. 2008; 40(2):189-97. PMC: 2682493. DOI: 10.1038/ng.75. View

13.

Willer C, Sanna S, Jackson A, Scuteri A, Bonnycastle L, Clarke R . Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet. 2008; 40(2):161-9. PMC: 5206900. DOI: 10.1038/ng.76. View

14.

Deloukas P, Kanoni S, Willenborg C, Farrall M, Assimes T, Thompson J . Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet. 2012; 45(1):25-33. PMC: 3679547. DOI: 10.1038/ng.2480. View

15.

Wilson P, DAgostino R, Levy D, Belanger A, Silbershatz H, Kannel W . Prediction of coronary heart disease using risk factor categories. Circulation. 1998; 97(18):1837-47. DOI: 10.1161/01.cir.97.18.1837. View

16.

Sarwar N, Sandhu M, Ricketts S, Butterworth A, Di Angelantonio E, Boekholdt S . Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet. 2010; 375(9726):1634-9. PMC: 2867029. DOI: 10.1016/S0140-6736(10)60545-4. View

17.

Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray K, Thompson A . Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009; 302(18):1993-2000. PMC: 3284229. DOI: 10.1001/jama.2009.1619. View

18.

Sarwar N, Danesh J, Eiriksdottir G, Sigurdsson G, Wareham N, Bingham S . Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation. 2006; 115(4):450-8. DOI: 10.1161/CIRCULATIONAHA.106.637793. View

19.

Abecasis G, Altshuler D, Auton A, Brooks L, Durbin R, Gibbs R . A map of human genome variation from population-scale sequencing. Nature. 2010; 467(7319):1061-73. PMC: 3042601. DOI: 10.1038/nature09534. View

20.

Haase C, 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. 2010; 95(12):E500-10. DOI: 10.1210/jc.2010-0450. View