title: Pharmacogenetic study of statin therapy and cholesterol reduction.
abstract: BACKGROUND
  Polymorphisms in genes involved in cholesterol synthesis, absorption, and transport may affect statin efficacy.
  
  
  OBJECTIVE
  To evaluate systematically whether genetic variation influences response to pravastatin therapy.
  
  
  METHODS
  The DNA of 1536 individuals treated with pravastatin, 40 mg/d, was analyzed for 148 single-nucleotide polymorphisms (SNPs) within 10 candidate genes related to lipid metabolism. Variation within these genes was then examined for associations with changes in lipid levels observed with pravastatin therapy during a 24-week period.
  
  
  METHODS
  Changes in lipid levels in response to pravastatin therapy.
  
  
  RESULTS
  Two common and tightly linked SNPs (linkage disequilibrium r2 = 0.90; heterozygote prevalence = 6.7% for both) were significantly associated with reduced efficacy of pravastatin therapy. Both of these SNPs were in the gene coding for 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the target enzyme that is inhibited by pravastatin. For example, compared with individuals homozygous for the major allele of one of the SNPs, individuals with a single copy of the minor allele had a 22% smaller reduction in total cholesterol (-32.8 vs -42.0 mg/dL [-0.85 vs -1.09 mmol/L]; P =.001; absolute difference, 9.2 mg/dL [95% confidence interval [CI], 3.8-14.6 mg/dL]) and a 19% smaller reduction in low-density lipoprotein (LDL) cholesterol (-27.7 vs -34.1 mg/dL [-0.72 vs -0.88 mmol/L]; P =.005; absolute difference, 6.4 mg/dL [95% CI, 2.2-10.6 mg/dL]). The association for total cholesterol reduction persisted even after adjusting for multiple tests on all 33 SNPs evaluated in the HMG-CoA reductase gene as well as for all 148 SNPs evaluated was similar in magnitude and direction among men and women and was present in the ethnically diverse total cohort as well as in the majority subgroup of white participants. No association for either SNP was observed for the change in high-density lipoprotein (HDL) cholesterol (P>.80) and neither was associated with baseline lipid levels among those actively treated or among those who did not receive the drug. Among the remaining genes, less robust associations were found for squalene synthase and change in total cholesterol, apolipoprotein E and change in LDL cholesterol, and cholesteryl ester transfer protein and change in HDL cholesterol, although none of these met our conservative criteria for purely pharmacogenetic effects.
  
  
  CONCLUSIONS
  Individuals heterozygous for a genetic variant in the HMG-CoA reductase gene may experience significantly smaller reductions in cholesterol when treated with pravastatin.
authors.affiliation: Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02215, USA.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.forename: David
authors.initials: D
authors.lastname: Posada
authors.forename: Lakshman
authors.initials: L
authors.lastname: Subrahmanyan
authors.forename: Nancy R
authors.initials: NR
authors.lastname: Cook
authors.forename: Vincent P
authors.initials: VP
authors.lastname: Stanton
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ridker
mesh_terms: D000368:Aged; D002784:Cholesterol / Q000097:blood* / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D005260:Female; D005838:Genotype; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017035:Pravastatin / Q000627:therapeutic use*
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D017035:Pravastatin