Lower LDL-C mediated by both NPC1L1 and HMGCR polymorphisms additively reduced the risk of CHD by 10.8% (OR 0.892; 95% CI 0.854-0.932) compared to the reference group.
Observational (n=108,376)
Mendelian randomization
Yes
Does lower LDL-C mediated by polymorphisms in NPC1L1, HMGCR, or both reduce the risk of coronary heart disease?
Genetic variants in NPC1L1 and HMGCR that lower LDL-C have an additive, log-linear effect on reducing the risk of coronary heart disease, supporting the combination of ezetimibe and statins.
Effect estimate: OR 0.892 (95% CI 0.854 to 0.932)
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.
Ference et al. (Wed,) conducted a observational in Coronary heart disease (n=108,376). Lower LDL-C mediated by NPC1L1 and HMGCR polymorphisms vs. Reference group was evaluated on CHD (fatal or nonfatal myocardial infarction) (OR 0.892, 95% CI 0.854 to 0.932). Lower LDL-C mediated by both NPC1L1 and HMGCR polymorphisms additively reduced the risk of CHD by 10.8% (OR 0.892; 95% CI 0.854-0.932) compared to the reference group.
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