title: Impact of common genetic variation on response to simvastatin therapy among 18 705 participants in the Heart Protection Study.
abstract: OBJECTIVE
  Statins reduce LDL cholesterol (LDL-C) and the risk of vascular events, but it remains uncertain whether there is clinically relevant genetic variation in their efficacy. This study of 18 705 individuals aims to identify genetic variants related to the lipid response to simvastatin and assess their impact on vascular risk response.
  
  
  RESULTS
  A genome-wide study of the LDL-C and apolipoprotein B (ApoB) response to 40 mg simvastatin daily was performed in 3895 participants in the Heart Protection Study, and the nine strongest associations were tested in 14 810 additional participants. Selected candidate genes were also tested in up to 18 705 individuals. There was 90% power to detect differences of 2.5% in LDL-C response (e.g. 42.5 vs. 40% reduction) in the genome-wide study and of 1% in the candidate gene study. None of the associations from the genome-wide study was replicated, and nor were significant associations found for 26 of 36 candidates tested. Novel lipid response associations with variants in LPA, CELSR2/PSRC1/SORT1, and ABCC2 were found, as well as confirmatory evidence for published associations in LPA, APOE, and SLCO1B1. The largest and most significant effects were with LPA and APOE, but were only 2-3% per allele. Reductions in the risk of major vascular events during 5 years of statin therapy among 18 705 high-risk patients did not differ significantly across genotypes associated with the lipid response.
  
  
  CONCLUSIONS
  Common genetic variants do not appear to alter the lipid response to statin therapy by more than a few per cent, and there were similar large reductions in vascular risk with simvastatin irrespective of genotypes associated with the lipid response to simvastatin. Consequently, their value for informing clinical decisions related to maximizing statin efficacy appears to be limited.
authors.affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK. jemma.hopewell@ctsu.ox.ac.uk
authors.forename: Jemma C
authors.initials: JC
authors.lastname: Hopewell
authors.forename: Sarah
authors.initials: S
authors.lastname: Parish
authors.forename: Alison
authors.initials: A
authors.lastname: Offer
authors.forename: Emma
authors.initials: E
authors.lastname: Link
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Jane
authors.initials: J
authors.lastname: Armitage
authors.forename: Rory
authors.initials: R
authors.lastname: Collins
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001055:Apolipoproteins B / Q000187:drug effects* / Q000235:genetics; D002318:Cardiovascular Diseases / Q000235:genetics / Q000517:prevention & control*; D008078:Cholesterol, LDL / Q000187:drug effects* / Q000235:genetics; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000235:genetics; D017270:Lipoprotein(a) / Q000235:genetics; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D020641:Polymorphism, Single Nucleotide; D019821:Simvastatin / Q000627:therapeutic use*
chemical_list: C000715087:ABCC2 protein, human; D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D017270:Lipoprotein(a); D000089762:Multidrug Resistance-Associated Protein 2; D019821:Simvastatin