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

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

Background

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).

Conclusion

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.

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