New genetic study highlights causal role of triglyceride-rich lipoproteins in coronary artery disease

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5 November 2013

This study showed that common genetic variants that influence plasma triglycerides levels are associated with coronary artery disease (CAD) risk. Given that plasma triglyceride levels are a marker for triglyceride-rich lipoproteins (TRLs), a key component of atherogenic dyslipidaemia, this study provides support for a causal role of TRLs in the development of CAD.

Do R, Willer CJ, Schmidt EM et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet 2013 Oct 6. doi: 10.1038/ng.2795. [Epub ahead of print].

STUDY SUMMARY

Objective

To evaluate the extent to which common genetic variants associated with low-density lipoprotein cholesterol (LDL C), high-density lipoprotein cholesterol (HDL-C) and triglycerides levels, influence CAD risk.

Study design

Meta-analysis of genetic variants for LDL-C, HDL-C or triglycerides; and a statistical framework analysis of data from a genome-wide association study (GWAS) of the effect of each variant on CAD risk

Study population

185 genetic variants mapped for LDL-C, HDL-C and/or triglycerides derived from a meta-analysis of 188,577 subjects(1); the GWAS involved 86,995 individuals (CARDIoGRAM study)(.2)

Primary variable

Extent of association of each variant with CAD risk

Methods

The authors evaluated the extent to which each variant was associated with triglycerides, LDL-C and HDL-C plasma levels, as well as CAD risk. If the variant that altered the lipid trait also altered disease risk to the same degree, it was assumed that the relationship between lipid and disease was causal. To isolate the effects of triglycerides, causal influences were investigated for each variant that had shown moderate to strong effects on triglycerides but minimal effects on LDL-C levels. A statistical framework that controls for pleiotropic effects on secondary lipid traits was used to test whether the effect size of each variant on triglycerides levels was linearly related to its effect size on CAD, before and after accounting for its potential effects on plasma LDL-C and/or HDL-C levels.

Main results

First, the study showed that 11 genetic variants had consistent direction and extent of association for both LDL-C and triglycerides. Five of these also conferred risk for CAD, and 10 of 11 showed a consistent direction of effect between lipids and CAD risk indicating that both lipid traits were factors in determining CAD risk. Secondly, in a subset of variants (n=44) with moderate to strong effects on triglycerides but minimal effects on LDL-C levels, there was a strong association between the effect on triglycerides levels and CAD risk. Thirdly, using a model which accounted for secondary effects on LDL-C and/or HDL-C, the authors showed that the effects of these variants on triglycerides levels were highly associated with their effect on CAD risk. This was especially the case for variants associated with loss of APOA5 or TRIB1 function, or gain of APOC3 function, and increased risk for CAD.

Author's conclusion

Based on these findings, the authors suggest that TRLs, for which triglycerides are a marker, causally influence risk for CAD.

COMMENT

Triglycerides are carried in the plasma, either in very low-density lipoproteins (VLDL) and their remnants under fasting conditions, or postprandially in chylomicrons and their remnants. Collectively these are referred to as TRLs. Evidence supports a role for TRLs, especially in the postprandial state, in the development and progression of atherosclerotic plaque.3,4 In animal models, cholesterol-rich TRL remnants were shown to have similar proatherogenic properties as LDL;5 a recent Mendelian randomisation study also provides evidence for a causal role of remnant cholesterol in ischaemic heart disease.6 Thus, there is a clear rationale to support the view that plasma levels of triglycerides, which are a marker of TRLs, capture several processes that promote atherosclerosis.

This genetic study provides further evidence linking TRL with a causal role in CAD. In particular there is strong evidence linking variants associated with loss of APOA5 or TRIB1 function, or gain of APOC3 function, with increased risk for CAD. The strengths of this study include the sample size, and the use of a statistical framework in an attempt to differentiate the effects of triglycerides on CAD risk from confounding effects due to LDL-C or HDL-C plasma levels.

The conclusion of this report is consistent with the view of the Residual Risk Reduction Initiative (R3i), that elevated TRLs and their remnants, a key component of atherogenic dyslipidaemia (commonly including low HDL-C and often an increase in the preponderance of small dense LDL), is a key driver of accelerated atherosclerosis and residual cardiovascular risk in patients on LDL-C lowering therapy.7 Recent Position papers from expert international societies also concur with an increasing role for TRLs.8,9 Indeed, with the failure of recent studies investigating HDL-targeted therapies on cardiovascular outcomes, there is an emerging consensus transferring from an HDL-based focus to that more directed towards TRL as a key modifiable lipid target beyond LDL-C to reduce residual cardiovascular risk. Thus, despite questions over the exact causal mechanisms implicated, therapeutic targeting of TRLs through lowering of elevated triglycerides may be an effective strategy for residual cardiovascular risk; a discussion carried forward in From the Editor’s Desk.

References

1. Global Lipids Genetics Consortium. Discovery and refinement of loci associated with lipid levels. Nat Genet 2013; Epub ahead of print (6 October 2013).
2. Schunkert H, König IR, Kathiresan S et al. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet 2011;43:333-8. doi: 10.1038/ng.784.
3. Ginsberg HN. New perspectives on atherogenesis. Role of abnormal triglyceride-rich lipoprotein metabolism. Circulation 2002;106;2137-2142
4. Proctor SD, Mamo JCL. Retention of fluorescent-labelled chylomicron remnants within the intima of the arterial wall – evidence that plaque cholesterol may be derived from post-prandial lipoproteins. Eur J Clin Invest 1998;28:497-504
5. Nordestgaard BG, Wootton R, Lewis B. Selective retention of VLDL, IDL, and LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo. Molecular size as a determinant of fractional loss from the intima-inner media. Arterioscler Thromb Vasc Biol 1995;15:534-42.
6. Varbo A, Benn M, Tybjærg-Hansen A, Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427–36.
7. Fruchart JC, Sacks FM, Hermans MP et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient. Diab Vasc Dis Res 2008;5:319-35.
8. Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61.
9. The International Atherosclerosis Society. An International Atherosclerosis Society Position Paper: Global recommendations for the management of dyslipidemia. Full report [http://www.athero.org/download/IASPPGuidelines_FullReport_2.pdf].