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

Abstract

Importance: Some cholesteryl ester transfer protein (CETP) inhibitors lower low-density lipoprotein cholesterol (LDL-C) levels without reducing cardiovascular events, suggesting that the clinical benefit of lowering LDL-C may depend on how LDL-C is lowered.

Objective: To estimate the association between changes in levels of LDL-C (and other lipoproteins) and the risk of cardiovascular events related to variants in the CETP gene, both alone and in combination with variants in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene.

Design, setting, and participants: Mendelian randomization analyses evaluating the association between CETP and HMGCR scores, changes in lipid and lipoprotein levels, and the risk of cardiovascular events involving 102 837 participants from 14 cohort or case-control studies conducted in North America or the United Kingdom between 1948 and 2012. The associations with cardiovascular events were externally validated in 189 539 participants from 48 studies conducted between 2011 and 2015.

Exposures: Differences in mean high-density lipoprotein cholesterol (HDL-C), LDL-C, and apolipoprotein B (apoB) levels in participants with CETP scores at or above vs below the median.

Main outcomes and measures: Odds ratio (OR) for major cardiovascular events.

Results: The primary analysis included 102 837 participants (mean age, 59.9 years; 58% women) who experienced 13 821 major cardiovascular events. The validation analyses included 189 539 participants (mean age, 58.5 years; 39% women) with 62 240 cases of coronary heart disease (CHD). Considered alone, the CETP score was associated with higher levels of HDL-C, lower LDL-C, concordantly lower apoB, and a corresponding lower risk of major vascular events (OR, 0.946 [95% CI, 0.921-0.972]) that was similar in magnitude to the association between the HMGCR score and risk of major cardiovascular events per unit change in levels of LDL-C (and apoB). When combined with the HMGCR score, the CETP score was associated with the same reduction in LDL-C levels but an attenuated reduction in apoB levels and a corresponding attenuated nonsignificant risk of major cardiovascular events (OR, 0.985 [95% CI, 0.955-1.015]). In external validation analyses, a genetic score consisting of variants with naturally occurring discordance between levels of LDL-C and apoB was associated with a similar risk of CHD per unit change in apoB level (OR, 0.782 [95% CI, 0.720-0.845] vs 0.793 [95% CI, 0.774-0.812]; P = .79 for difference), but a significantly attenuated risk of CHD per unit change in LDL-C level (OR, 0.916 [95% CI, 0.890-0.943] vs 0.831 [95% CI, 0.816-0.847]; P < .001) compared with a genetic score associated with concordant changes in levels of LDL-C and apoB.

Conclusions and relevance: 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 levels and a corresponding risk of cardiovascular events 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 levels may therefore depend on the corresponding reduction in apoB-containing lipoprotein particles.

Figure 1.. Study Design

CARDIoGRAMplusC4D indicates Coronary Artery Disease Genome Wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics Consortium; CETP, cholesteryl ester transfer protein; HMGCR, 3-hydroxy-3-methyl-glutaryl-CoA reductase; LDL-C, low-density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin/kexin type 9.

Figure 2.. Association of CETP Score With Risk of Major Cardiovascular Events Among 102 837 Participants From 14 Cohort or Case-Control Studies

All information derived from the individual-participant data. A total of 102 837 participants who experienced a total of 13 821 first major cardiovascular events were included in the analysis. Among all participants, median cholesteryl ester transfer protein (CETP) genetic score was 34.8 (interquartile range [IQR], 28.3-41.1; range, 0-54.3). For participants in the group with CETP scores below the median, median CETP score was 28.2 (IQR, 23.3-32.0; range, 0-34.7). For participants in the group with CETP scores equal to or above the median, median CETP score was 41.1 (IQR, 37.9-44.8; range, 34.8-54.3). Higher scores indicate a greater number of high-density lipoprotein cholesterol (HDL-C)–raising alleles (weighted by the effect of each allele on HDL-C level) and is analogous to treatment with increasingly potent CETP inhibitors. Lipid and lipoprotein values are presented in mg/dL (to convert HDL-C and low-density lipoprotein cholesterol [LDL-C] values to mmol/L, multiply by 0.0259) as the difference in mean value for each group compared with the reference group, with 95% confidence intervals. Associations with major cardiovascular events were calculated using an inverse variance–weighted fixed-effects meta-analysis of the study-specific estimates of effect. In panels B and C, the association between the CETP score and risk of major cardiovascular events is compared with the association between the risk of major cardiovascular events and genetic scores consisting of variants in the 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) gene (encodes the target of statins), proprotein convertase subtilisin/kexin type 9 (PCSK9) gene (encodes target of PCSK9 inhibitors), and Niemann-Pick C1-Like 1 intracellular cholesterol transporter 1 (NPC1L1) gene (encodes target of ezetimibe). All associations between the genetic scores and risk of major cardiovascular events are standardized per 10-mg/dL lower level of LDL-C (panel B) or 10-mg/dL lower level of apolipoprotein B (apoB) (panel C) and measured in the overall sample of studies that contributed individual-participant data. Data markers indicate point estimates of effect and are of equal size because the analysis compared approximately equal-sized groups divided by the median CETP score value or quartiles of the CETP score (panel A). OR indicates odds ratio.

Figure 3.. Separate and Combined Effects of the CETP and HMGCR Scores on Risk of Major Cardiovascular Events Among 102 837 Participants From 14 Cohort or Case-Control Studies

All information derived from the individual-participant data. A total of 102 837 participants who experienced a total of 13 821 first major cardiovascular events were included in the analysis. Among all participants, the median cholesteryl ester transfer protein (CETP) genetic score was 34.8 (interquartile range [IQR], 28.3-41.1; range, 0-54.3). The median CETP and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) score, IQR, and range of values for each group is presented in Table 2. Lipid and lipoprotein values are presented in mg/dL (to convert high-density lipoprotein cholesterol [HDL-C] and low-density lipoprotein cholesterol [LDL-C] values to mmol/L, multiply by 0.0259) as the difference in mean value for each group compared with the reference group, with 95% confidence intervals. Associations with major cardiovascular events were calculated using an inverse variance–weighted fixed-effects meta-analysis of the study-specific estimates of effect. In panel B, the study population was first divided into 2 groups based on whether the HMGCR score was below or equal to or greater than the median value. The association between the CETP score and the risk of major cardiovascular events was then estimated modeling the CETP score as a continuous variable scaled to the lipid effects in the dichotomous score analysis. There was evidence for effect modification of the HMGCR score on the association between the CETP genetic score and the risk of major cardiovascular events (P = .04). Data markers indicate point estimates of effect and are of equal size because the analysis compared approximately equal-sized groups divided into a factorial analysis (panel A) or the median HMGCR score value (panel B). Error bars represent 95% confidence intervals. apoB indicates apolipoprotein B; OR, odds ratio.

Figure 4.. Association of Genetic Variants With Naturally Occurring Discordance Between Changes in Concentrations of LDL-C and apoB and the Risk of CHD Among CARDIoGRAMplusC4D Consortium Participants

Analyses are based on summary data from up to 62 240 participants with coronary heart disease (CHD) and 127 299 control participants from the Coronary Artery DIsease Genome Wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics (CARDIoGRAMplusC4D) Consortium. Effect sizes are standardized per 10-mg/dL lower level of low-density lipoprotein cholesterol (LDL-C) or 10-mg/dL lower level of apolipoprotein B (apoB). MR-Egger regression estimates are presented for sensitivity analyses. Data markers indicate point estimates of effect; error bars, 95% confidence intervals.