Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 × 2 factorial Mendelian randomization study

Abstract

Background: Considerable uncertainty exists as to whether lowering low-density lipoprotein cholesterol (LDL-C) by inhibiting the Niemann-Pick C1-Like 1 (NPC1L1) receptor with ezetimibe, either alone or in combination with a 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor (statin), will reduce the risk of coronary heart disease (CHD).

Objectives: This study evaluated the effect of naturally random allocation to lower LDL-C mediated by polymorphisms in the NPC1L1 gene (target of ezetimibe), the HMGCR gene (target of statins), or both (target of combination therapy) on the risk of CHD.

Methods: We constructed NPC1L1 and HMGCR genetic LDL-C scores to naturally randomize participants into 4 groups: reference, lower LDL-C mediated by NPC1L1 polymorphisms, lower LDL-C mediated by HMGCR polymorphisms, or lower LDL-C mediated by polymorphisms in both NPC1L1 and HMGCR. We compared the risk of CHD (fatal or nonfatal myocardial infarction) among each group using a 2 × 2 factorial mendelian randomization study design.

Results: A total of 108,376 persons (10,464 CHD events) from 14 studies were included. There were no significant differences in baseline characteristics among the 4 groups, thus confirming that allocation was random. Compared to the reference group, the NPC1L1 group had 2.4 mg/dl lower LDL-C and 4.8% lower risk of CHD (odds ratio [OR]: 0.952, 95% confidence interval [CI]: 0.920 to 0.985); whereas the HMGCR group had 2.9 mg/dl lower LDL-C and a similar 5.3% lower risk of CHD (OR: 0.947, 95% CI: 0.909 to 0.986). The group with lower LDL-C mediated by both NPC1L1 and HMGCR polymorphisms had 5.8 mg/dl additively lower LDL-C and a 10.8% log-linearly additive lower risk of CHD (OR: 0.892, 95% CI: 0.854 to 0.932).

Conclusions: The effect of lower LDL-C on the risk of CHD mediated by polymorphisms in NPC1L1, HMGCR, or both is approximately the same per unit lower LDL-C and log-linearly proportional to the absolute exposure to lower LDL-C.

Keywords: PCSK9; ezetimibe; genetic association; statins.

Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

FIGURE 1. Design of 2 × 2 Factorial Mendelian Randomization Study

Each subject was first randomly allocated into 1 of 2 groups based on whether their HMGCR LDL-C score was above or below the median, and then randomly allocated into 1 of 2 further groups based on whether their NPC1L1 LDL-C score was above or below the median using a factorial design. This process naturally randomized all subjects into 1 of 4 groups: the reference group (analogous to a placebo group), a group with lower LDL-C mediated polymorphisms in the NPC1L1 gene (analogous to treatment with ezetimibe), a group with lower LDL-C mediated polymorphisms in the HMGCR gene (analogous to treatment with a statin), and a group with lower LDL-C mediated by the combined effect of polymorphisms in both the NPC1L1 and HMGCR genes (analogous to treatment with combination ezetimibe and a statin).

FIGURE 2. Effect of Lower LDL-C Mediated by Polymorphisms in NPC1L1, HMGCR, or Both

Boxes represent point estimates and lines represent 95% CIs. Reference group is the group with both NPC1L1 and HMGCR LDL-C scores below median. CI = confidence interval; LDL-C = low-density lipoprotein cholesterol; HMGCR = hydroxymethyl glutaryl coenzyme A reductase; NPC1L1 = Niemann-Pick C1-Like 1.

FIGURE 3. Comparison of Effect of 10 mg/dl Lower LDL-C on Risk of CHD Mediated by Polymorphisms in the NPC1L1 and HMGCR Genetic LDL-C Scores in Up to 62,240 Cases of CHD and 127,299 Control Subjects

Boxes represent point estimates and lines represent 95% CIs. Abbreviations as in Figure 2.

FIGURE 4. Comparison of Effect of 10 mg/dl Lower LDL-C on Risk of CHD Mediated by Polymorphisms in the LDL-C Receptor Pathway in Up to 63,746 Cases of CHD and 130,681 Control Subjects

Boxes represent point estimates and lines represent 95% CIs. Point estimates (and CI) adjusted per unit lower LDL-C using the usual ratio of effect estimates method.

CENTRAL ILLUSTRATION. 2 × 2 Factorial Mendelian Randomization Study: Log-Linear Association Between Genetically and Pharmacologically Mediated Lower Low-Density Lipoprotein Cholesterol and Risk of Coronary Heart Disease

Boxes represent proportional risk reduction (1–OR) of CHD for each exposure allele, genetic score, or randomized trial plotted against the absolute magnitude of lower LDL-C associated with that allele or genetic score; or the absolute difference in LDL-C between treatment groups for each trial. Vertical lines represent 1 SE above and below point estimate of proportional risk reduction. SNPs, genetic scores, and trials are plotted in order of increasing absolute magnitude of effect on lower LDL-C. The lines (which are forced to pass through the origin) represent the increase in proportional risk reduction of CHD per unit lower LDL-C. In the top line, the salmon boxes represent results of the 2 × 2 factorial mendelian randomization study and the blue boxes represent results derived from CARDIoGRAMplusC4D consortia data. In the lower line, the salmon box represents the results of the IMPROVE-IT trial and the blue boxes represent the results of prior statin trials. CHD = coronary heart disease; IMPROVE-IT = IMProved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL-C = low-density lipoprotein cholesterol; OR = odds ratio; SE = standard error; SNP = single-nucleotide polymorphism.