Association of Genetic Variants Related to CETP Inhibitors and Statins With Lipoprotein Levels and CV Risk

Study Questions:

Is there an association between changes in low-density lipoprotein cholesterol (LDL-C) (and other lipoproteins) and the risk of cardiovascular events (CVEs) due to variants in the cholesterol ester transfer protein (CETP) gene, both alone and in combination with variants in the HMGCR gene?


Mendelian randomization analyses were performed in the REVEAL trial to evaluate the association between CETP and HMGCR scores, changes in lipid and lipoprotein levels, and the risk of CVEs involving participants from 14 cohort or case-control studies conducted in North America between 1948 and 2012. The associations with CVEs were externally validated in participants from 48 studies conducted between 2011 and 2015. The CETP genetic score was constructed by combining all variants within 100kb on either side of the CETP gene that were conditionally associated with HDL-C. Measured outcomes included the differences in mean HDL-C, LDL-C, and apolipoprotein B (apoB) levels comparing participants with CETP scores equal to and above or below the median. Primary outcomes were the odds ratio (OR) for major vascular events (MVEs).


A total of 102,837 participants (mean age, 59.9 years; 58% women) who experienced 13,821 MVEs were included in the primary analysis, and 189,539 participants (mean age, 58.5 years; 39% women) including 62,240 cases of coronary heart disease (CHD) were included in the validation analyses. Considered alone, the CETP score was associated with higher HDL-C, lower LDL-C, concordantly lower apoB, and a corresponding lower risk of MVEs (OR, 0.946; 95% confidence interval [CI], 0.921-0.972) that was very similar in magnitude to the association between the HMGCR score and risk of MVEs per unit change in LDL-C (and apoB). By contrast, when combined with the HMGCR score, the CETP score was associated with the same reduction in LDL-C, but an attenuated reduction in apoB and a corresponding attenuated nonsignificant risk of MVEs (OR, 0.985; 95% CI, 0.955-1.015). In external validation analyses, a genetic score consisting of variants with naturally occurring discordance between LDL-C and apoB was associated with a very similar risk of CHD per unit change in apoB (OR, 0.782; 95% CI, 0.720-0.845 vs. OR, 0.793; 95% CI, 0.774-0.812; p for difference 0.79), but a significantly attenuated risk of CHD per unit change in LDL-C (OR, 0.916, 95% CI, 0.890-0.943 vs. OR, 0.831; 95% CI, 0.816-0.847; p < 0.001) compared to a genetic score associated with concordant changes in LDL-C and apoB.


Combined exposure to variants in the genes that encode the targets of CETP inhibitors and statins was associated with discordant reductions in LDL-C and apoB, and a corresponding risk of CVEs that was proportional to the attenuated reduction in apoB, but significantly less than expected per unit change in LDL-C. The clinical benefit of lowering LDL-C may therefore depend on the corresponding reduction in apoB-containing lipoprotein particles.


The complicated study design required three separate analyses with variable data sources to satisfy three objectives that were required to test the hypothesis. The rationale for this study came from the clinical trial results that found some CETP inhibitors alone or in combination with statins lower LDL-C without reducing CVEs, suggesting that the clinical benefit of lowering LDL-C may depend on how LDL-C is lowered. From the lipid hypothesis, the results support the conclusions that lowering LDL-C alone will not be as valuable as also reducing triglyceride-rich remnants. The value of Mendelian randomization analysis for predicting effects of drugs within classes and with varying targets seems often to hit a home run. The tool has the potential to predict outcome and avoid very expensive clinical trials.

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