Author + information
- Received September 30, 2014
- Revision received January 30, 2015
- Accepted February 3, 2015
- Published online April 21, 2015.
- Brian A. Ference, MD, MPhil, MSc∗,†,‡∗ (, )
- Faisal Majeed, MBBS∗,
- Raju Penumetcha, MD‡,
- John M. Flack, MD, MPH∗,‡ and
- Robert D. Brook, MD§
- ∗Division of Translational Research and Clinical Epidemiology, Wayne State University School of Medicine, Detroit, Michigan
- †Division of Cardiovascular Medicine, Wayne State University School of Medicine, Detroit, Michigan
- ‡Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan
- §Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, Michigan
- ↵∗Reprint requests and correspondence to:
Dr. Brian A. Ference, Division of Translational Research and Clinical Epidemiology, Division of Cardiovascular Medicine, Wayne State University School of Medicine, UHC 2E2, Detroit, Michigan 48202.
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.
This research was funded in part by an investigator-initiated grant from Merck & Co. The funding body had no role in the design, conduct, or analysis of the study; did not have access to any of the data; did not participate in drafting of the manuscript; and did not participate in the decision to submit for publication.
Dr. Ference has reported significant research grants, modest service as a consultant and advisory board member, and has received modest honoraria from Merck. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received September 30, 2014.
- Revision received January 30, 2015.
- Accepted February 3, 2015.
- American College of Cardiology Foundation