Abstract 19754: Effect of Naturally Random Allocation to Lower LDL-C Mediated by Polymorphisms in NPC1L1, HMGCR or Both on the Risk of Coronary Heart Disease: a 2x2 Factorial Mendelian Randomization Study
Introduction: Considerable uncertainty exists as to whether lowering LDL cholesterol (LDL-C) by inhibiting the NPC1L1 receptor with ezetimibe, either alone or in combination with an HMGCR inhibitor (statin), will reduce the risk of coronary heart disease (CHD).
Hypothesis: We evaluated the effect of naturally random allocation to lower LDL-C mediated by polymorphisms in the NPC1L1 gene (as a proxy for treatment with ezetimibe), the HMGCR gene (as a proxy for treatment with a statin), or both (as a proxy for combination therapy) on the risk of CHD.
Methods: We constructed an HMGCR genetic LDL-C score and an NPC1L1 genetic LDL-C score. We used these genetic scores to naturally randomize participants into one of four groups: reference, lower LDL-C mediated by NPC1L1 polymorphisms, lower LDL-C mediated by HMGCR polymorphisms, or lower LDL-C mediated by the combined effect of polymorphisms in both NPC1L1 and HMGCR. We then compared the risk of CHD (fatal or non-fatal myocardial infarction) among each group using a 2x2 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 any baseline characteristics among the four groups, thus demonstrating that allocation was random. As compared to the reference group, the group with lower LDL-C mediated by NPC1L1 polymorphisms had 0.08 mmol/L lower LDL-C and a 6.5% lower risk of CHD (RR: 0.935, 95%CI: 0.915-0.955); while the group with lower LDL-C mediated by HMGCR polymorphisms had 0.09 mmol/L lower LDL-C and a similar 7.0% lower risk of CHD (RR: 0.930, 95%CI: 0.931-0.948). The group with lower LDL-C mediated by the combined effect of polymorphisms in both NPC1L1 and HMGCR had an additively larger 0.17 mmol/L lower LDL-C and a correspondingly greater 13.7% lower risk of CHD (RR: 0.863, 95%CI: 0.836-0.890).
Conclusions: Lower LDL-C mediated by genetic inhibition of NPC1L1, HMGCR, or both is associated with a lower risk of CHD that is proportional to the magnitude of exposure to lower LDL-C. Therefore, lowering LDL-C by inhibiting NPC1L1 with ezetimibe, either alone or in combination with an HMGCR inhibitor statin, should result in a reduction in the risk of CHD that is proportional to the absolute reduction in LDL-C.
Author Disclosures: B.A. Ference: Research Grant; Significant; Merck. Other Research Support; Modest; NHLBI. Honoraria; Modest; Merck, Celera Genomics, Quest Diagnostics. Consultant/Advisory Board; Modest; Merck. F. Majeed : None. R.D. Brook: None. L. Hedquist: None. R. Penumetcha: None. J.M. Flack: None.
- © 2014 by American Heart Association, Inc.