title: 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).
  
  
  OBJECTIVE
  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.
authors.affiliation: 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. Electronic address: bference@med.wayne.edu.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Ference
authors.affiliation: Division of Translational Research and Clinical Epidemiology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Faisal
authors.initials: F
authors.lastname: Majeed
authors.affiliation: Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Raju
authors.initials: R
authors.lastname: Penumetcha
authors.affiliation: Division of Translational Research and Clinical Epidemiology, Wayne State University School of Medicine, Detroit, Michigan; Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: John M
authors.initials: JM
authors.lastname: Flack
authors.affiliation: Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Brook
mesh_terms: D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics*; D003327:Coronary Disease / Q000097:blood / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D011110:Polymorphism, Genetic; D018570:Risk Assessment
chemical_list: D008078:Cholesterol, LDL; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C410800:NPC1L1 protein, human; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases
keywords: PCSK9; ezetimibe; genetic association; statins