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Macrovascular Residual Risk Studies

13 March 2014
Mendelian randomization study supports a causal effect of triglycerides in coronary heart disease risk
This Mendelian randomization analysis in over 62 000 subjects with >12,000 coronary heart disease (CHD) events supports a causal effect of triglycerides. However, the evidence is less certain for a role for high-density lipoprotein cholesterol (HDL-C).
Holmes MV, Asselbergs FW, Palmer TM et al. Mendelian randomization of blood lipids for coronary heart disease. Eur Heart J 2014; doi:10.1093/eurheartj/eht571.
Objective: To investigate the causal role of HDL-C and triglycerides in CHD
Study design: A Mendelian randomization approach based on individual subject data was used for this analysis.
Study population:

Data from 17 studies including 62,199 individuals of European origin with 12,099 incident or prevalent CHD cases.

Primary variable:

• The combination of incident or prevalent CHD events
• A subsidiary analysis was limited to incident CHD cases (i.e. cases accrued during the follow-up period)


Weighted allele scores based on single nucleotide polymorphisms (SNPs) with known associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C) were developed. Each lipid trait had two scores; the first was unrestricted, including all independent SNPs associated with the lipid trait identified from a previous meta-analysis (n= 66,240 subjects)1, and the second was a restricted score, in which any SNPs also associated with either of the other two lipid traits were excluded. If more than one SNP was present at a gene locus, only the SNP with the lowest p-value for the target lipid trait was included in the allele score.

The numbers of SNPs included in unrestricted and restricted scores for each lipid trait are summarised below.

Lipid trait

No. of SNPs in unrestricted score

No. of SNPs in restricted score











Key findings are summarised in Table 1.
Both scores for LDL-C were associated with CHD.
For HDL-C, the unrestricted score associated with CHD; however, this association was no longer evident after adjustment for triglycerides, LDL-C, or statin use. Additionally, the restricted score for HDL-C was not associated with CHD. For triglycerides, both unrestricted and restricted scores were associated with CHD. Adjustment for LDL-C resulted in only a small change in this risk estimate (odds ratio 1.31, 95% CI 0.86 to 1.98).  However, adjustment of the unrestricted score for HDL‑C, LDL-C, and statin use attenuated this association.

Table 1. Odds ratio for CHD with 95% CI per 1 mmol/L increase (HDL-C and LDL-C) or 1 log-unit increase (triglycerides) 

Lipid trait

Unrestricted score

Adjusted unrestricted score*

Restricted score


1.78 (1.58-2.01)

1.26 (1.04-1.52)

1.92 (1.68-2.19)


0.53 (0.40-0.70)

0.81 (0.44-1.46)

0.91 (0.42-1.98)


1.62 (1.24-2.11)

1.01 (0.59-1.75)

1.61 (1.00-2.59)

* Adjustment for the two other lipid traits and statin use

Authors’ conclusion: These genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.


This landmark genetic study adds to an increasing body of evidence supporting a causal role for elevated triglycerides, a marker of triglyceride-rich lipoproteins and their remnants, in CHD.1-3 The findings are strengthened by the size, methodological approach and use of individual subject data in this analysis.

It is notable that the risk for CHD associated with triglyceride-raising was similar for restricted and unrestricted scores (see Table 1). Adjustment of the unrestricted score for LDL-C concentration had only a small effect on this risk estimate (odds ratio 1.31 (95% CI 0.86 - 1.98). While this association was essentially null after further adjustment of the unrestricted score for HDL-C, it is highly relevant that two out of the three approaches provide evidence of a causal role of triglycerides in CHD. Metabolomic approaches which enable partitioning of triglyceride-rich lipoproteins according to size and composition may help to further understanding of the causality of these lipoproteins in CHD.

In contrast, the evidence for HDL-C is uncertain. In this analysis, restriction to alleles that were solely linked with HDL-C raising and did not influence triglycerides or LDL-C attenuated the association between HDL-C plasma concentration and CHD risk. This finding is consistent with results from another genetic analysis, which failed to show a causal association between genetically raised plasma HDL-C concentration due to the presence of a loss of function SNP in the endothelial lipase gene (LIPG Asn396Ser) and risk for myocardial infarction (MI).4 It is also relevant that there have been recent casualties among trials testing novel HDL-raising therapies (such as dal-OUTCOMES with the cholesteryl ester transfer protein inhibitor dalcetrapib).5 Some have suggested that these findings may relate to the fact that HDL-C plasma concentration is a poor surrogate of the relationship between HDL and CHD risk, and does not take into consideration the fact that HDL is a heterogeneous population of lipoprotein particles with distinct apolipoprotein and lipid composition that dictate their atheroprotective or proatherogenic function. Indeed, both HDL particle concentration (albeit a static measure) and HDL functionality have been suggested as more appropriate markers of CHD risk.

References 1. 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.
2. Varbo A, Benn M, Tybjærg-Hansen A et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427–36.
3. Do R, Willer CJ, Schmidt EM et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet 2013;45:1345-52.
4. Voight BF, Peloso GM, Orho-Melander M et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012;380:572-80.
5. Schwartz GG, Olsson AG, Abt M et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089-99.
Key words triglycerides; high-density lipoprotein cholesterol; coronary risk; causality