title: Identification of genetic variants associated with response to statin therapy.
abstract: OBJECTIVE
  The purpose of this study was to test the association between polymorphisms in genes involved in either LDL cholesterol (LDL-C) metabolism or statin pharmacokinetics and LDL-C reduction with statins.
  
  
  RESULTS
  49 tagging and candidate polymorphisms in 9 genes were genotyped in 1507 post-ACS subjects randomized to atorvastatin or pravastatin. Two polymorphisms (rs7412, rs429358) that define the epsilon2, epsilon3, and epsilon4 isoforms of apolipoprotein E were significantly associated with percent reduction in LDL-C with atorvastatin (epsilon2 carriers 53.8%, epsilon3/epsilon3 48.1%, and epsilon4 carriers 46.4%, respectively, P=0.00039) and replicated in the pravastatin arm (epsilon2 carriers 22.1%, epsilon3/epsilon3 21.8%, and epsilon4 carriers 16.6%, respectively, P=0.00038). The proportion of subjects achieving an LDL-C < or =70 mg/dL at day 30 was higher for epsilon2 than epsilon4 carriers (P=1.3 x 10(-5)). In the pravastatin group, the triallelic rs2032582 variant (G2677T/A) in ABCB1 was associated with the percent reduction in LDL-C (GG 23.3%, non-G heterozygote 20.3%, and non-G homozygote 17.4%, P=0.042).
  
  
  CONCLUSIONS
  Carriers of APOE epsilon2 versus epsilon4 had significantly greater LDL-C reduction with atorvastatin and with pravastatin, and more frequently achieved a guideline-recommended LDL-C < or =70 mg/dL. Polymorphisms in triallelic G2677T/A variant in ABCB1 were associated with the degree of LDL-C lowering with pravastatin.
authors: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. jmega@partners.org
authors: Jessica L
authors: JL
authors: Mega
authors: David A
authors: DA
authors: Morrow
authors: Alison
authors: A
authors: Brown
authors: Christopher P
authors: CP
authors: Cannon
authors: Marc S
authors: MS
authors: Sabatine
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D054058:Acute Coronary Syndrome / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D000069059:Atorvastatin; D001711:Biotransformation / Q000235:genetics; D008078:Cholesterol, LDL / Q000097:blood; D006239:Haplotypes; D006538:Heptanoic Acids / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D017410:Practice Guidelines as Topic; D017035:Pravastatin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011758:Pyrroles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001057:Apolipoproteins E; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin; D017035:Pravastatin