Macrovascular Residual Risk Studies

COMMENT

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.