title: Pharmacogenetic predictors of statin-mediated low-density lipoprotein cholesterol reduction and dose response.
abstract: BACKGROUND
  There is interindividual variation in low-density lipoprotein cholesterol (LDLc) lowering by statins and limited study into the genetic associations of the dose dependant LDLc lowering by statins.
  
  
  RESULTS
  Five hundred nine patients with hyperlipidemia were randomly assigned atorvastatin 10 mg, simvastatin 20 mg, or pravastatin 10 mg (low-dose phase) followed by 80 mg, 80 mg, and 40 mg (high-dose phase), respectively. Thirty-one genes in statin, cholesterol, and lipoprotein metabolism were sequenced and 489 single nucleotide polymorphisms with minor allele frequencies >2% were tested for associations with percentage LDLc lowering at low doses using multivariable adjusted general linear regression. Significant associations from the analysis at low dose were then repeated at high-dose statins. At low doses, only 1 single nucleotide polymorphism met our experiment-wide significance level, ABCA1 rs12003906. Twenty-six subjects carried the minor allele of rs12003906, which was associated with an attenuated LDLc reduction (LDLc reduction in carriers versus noncarriers -24.1+/-2.6% versus -32.2+/-1.5%; P=0.0001). In addition, we replicated the association with the APOE epsilon3 allele and a reduced LDLc reduction. At high doses, carriers of the minor allele of ABCA1 rs12003906 and the APOE epsilon3 allele improved their LDLc reduction but continued to have a diminished LDLc reduction compared with noncarriers (-30.5+/-4.0% versus -42.0+/-2.4%; P=0.005) and (-38.5+/-1.9% versus -45.3+/-2.8%; P=0.009), respectively.
  
  
  CONCLUSIONS
  An intronic single nucleotide polymorphism in ABCA1 and the APOE epsilon3 allele are associated with reduced LDLc lowering by statins and identify individuals who may be resistant to maximal LDLc lowering by statins.
authors.affiliation: Division of Cardiovascular Medicine, the Institute for Genome & Science Policy, and the Center for Human Genetics, Duke University, Durham, NC 27708, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Voora
authors.forename: Svati H
authors.initials: SH
authors.lastname: Shah
authors.forename: Carol R
authors.initials: CR
authors.lastname: Reed
authors.forename: Jun
authors.initials: J
authors.lastname: Zhai
authors.forename: David R
authors.initials: DR
authors.lastname: Crosslin
authors.forename: Chad
authors.initials: C
authors.lastname: Messer
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Salisbury
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Ginsburg
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D053318:Apolipoprotein E3 / Q000235:genetics; D000069059:Atorvastatin; D008078:Cholesterol, LDL / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D006949:Hyperlipidemias / Q000188:drug therapy / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017035:Pravastatin / Q000008:administration & dosage / Q000627:therapeutic use; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use; D012044:Regression Analysis; D019821:Simvastatin / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D053318:Apolipoprotein E3; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin; D019821:Simvastatin; D017035:Pravastatin