Physicians' Academy for Cardiovascular Education

Causal link between triglycerides and coronary heart disease, but role for HDL-c less clear

Holmes MV Eur Heart J. 2015

Mendelian randomization of blood lipids for coronary heart disease

Holmes MV, Asselbergs FW, Palmer TM et al.,
Eur Heart J. 2015 Mar 1;36(9):539-50. doi: 10.1093/eurheartj/eht571


The causal relevance of HDL-c and triglyceride (TG) levels for coronary heart disease (CHD) events is uncertain. While observational studies have shown clear associations between HDL-c or TG and CHD [1], randomised trials evaluating drugs that modify these factors have not shown a benefit [2-4].
Mendelian randomisation can help to evaluate the causal relevance of biomarkers, by exploiting the natural randomised allocation of allelic variation in genes affecting their level [5,6].
Recent studies have shown that single nucleotide polymorphisms (SNPs) associated with the major blood lipid fractions are distributed across many genetic loci, which are inherited independently and affect lipid levels in an approximate additive fashion [7-9].
This study therefore used multiple independent SNPs as instrumental variables in a Mendelian randomisation approach, thus preventing the previously often seen limitation that a study investigated a single SNP with a weak, non-exclusive effect on the lipid target. Individual data of 17 studies encompassing data of 62199 individuals of European origin were analysed, in whom 12099 incident or prevalent CHD cases. Unrestricted scores for for instance HDL-C therefore consisted of all SNPs associated with HDL-c, and the restricted allele score comprised only SNPs that did not associate with either triglycerides or LDL-C.

Main results

  • A genetically instrumented 1 mmol/L increment in LDL-c yielded an OR for CHD of 1.78 (95%CI: 1.58-2.01) for the unrestricted, and 1.92 (95%CI: 1.68-2.19) restricted allele score.
  • A genetically instrumented 1 mmol/L increment in HDL-c yielded an OR for CHD of 0.53 (95%CI: 0.40-0.70) for the unrestricted, and 0.91 (95%CI: 0.42-1.98) restricted allele score.
  • A genetically instrumented 1 log-unit increment in TG yielded an OR for CHD of 1.62 (95%CI: 1.24-2.11) for the unrestricted, and 1.61 (95%CI: 1.00-2.59) restricted allele score.
  • The estimate of the HDL-c allele score showed more marked effects on the association with CHD events upon sequential adjustment for LDL-c, TGs and statin use, than did similar adjustments of the LDL-c allel score. The association between unrestricted HDL-c allel score with CHD events was weakened when adjusting for TG.
    Adjustment of the estimate of the TG allele score for HDL-c changed OR: 1.38 (95%CI: 0.98-1.94) to OR: 0.97 (95%CI: 0.64-1.49).


This study confirmed the causal role of LDL-c in CHD risk, and provides support for a causal role of TGs in CHD. The existence of a causal link between HDL-c levels and CHD is less certain, although possible.
The findings may suggest that a treatment that lowers TGs as well as increases HDL-c levels may be beneficial in the prevention of CHD events, while only targeting TGs may not be effective. The role of HDL-c on CHD risk requires further investigation.
Find this article online at Eur Heart J.


1. Di Angelantonio E, Sarwar N, Perry P, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993–2000.
2. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089–2099.
3. Keech A, Simes RJ, Barter P, 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 2005;366:1849–1861.
4. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109–2122.
5. Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey Smith G. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med 2008;27:1133–1163.
6. Hingorani A, Humphries S. Nature’s randomised trials. Lancet 2005;366: 1906–1908.
7. Teslovich TM, Musunuru K, Smith AV, et al. Utility of genetic determinants of lipids and cardiovascular events in assessing risk. Nat Rev Cardiol 2011;8:207–221.
8. Holmes MV, Harrison S, Talmud PJ, Hingorani AD, Humphries SE. Utility of genetic determinants of lipids and cardiovascular events in assessing risk. Nat Rev Cardiol 2011;8:207–221.
9. Asselbergs FW, Guo Y, van Iperen EP, et al. Large-scale genecentric meta-analysis across 32 studies identifies multiple lipid loci. Am J Hum Genet 2012;91:823–838.