title: Hepatic metabolism and transporter gene variants enhance response to rosuvastatin in patients with acute myocardial infarction: the GEOSTAT-1 Study.
abstract: BACKGROUND
  Pharmacogenetics aims to maximize benefits and minimize risks of drug treatment. Our objectives were to examine the influence of common variants of hepatic metabolism and transporter genes on the lipid-lowering response to statin therapy.
  
  
  RESULTS
  The Genetic Effects On STATins (GEOSTAT-1) Study was a genetic substudy of Secondary Prevention of Acute Coronary Events-Reduction of Cholesterol to Key European Targets (SPACE ROCKET) (a randomized, controlled trial comparing 40 mg of simvastatin and 10 mg of rosuvastatin) that recruited 601 patients after myocardial infarction. We genotyped the following functional single nucleotide polymorphisms in the genes coding for the cytochrome P450 (CYP) metabolic enzymes, CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C), CYP2C19*2 (681G>A), CYP3A5*1 (6986A>G), and hepatic influx and efflux transporters SLCO1B1 (521T>C) and breast cancer resistance protein (BCRP; 421C>A). We assessed 3-month LDL cholesterol levels and the proportion of patients reaching the current LDL cholesterol target of <70 mg/dL (<1.81 mmol/L). An enhanced response to rosuvastatin was seen for patients with variant genotypes of either CYP3A5 (P=0.006) or BCRP (P=0.010). Furthermore, multivariate logistic-regression analysis revealed that patients with at least 1 variant CYP3A5 and/or BCRP allele (n=186) were more likely to achieve the LDL cholesterol target (odds ratio: 2.289; 95% CI: 1.157, 4.527; P=0.017; rosuvastatin 54.0% to target vs simvastatin 33.7%). There were no differences for patients with variants of CYP2C9, CYP2C19, or SLCO1B1 in comparison with their respective wild types, nor were differential effects on statin response seen for patients with the most common genotypes for CYP3A5 and BCRP (n=415; odds ratio: 1.207; 95% CI: 0.768, 1.899; P=0.415).
  
  
  CONCLUSIONS
  The LDL cholesterol target was achieved more frequently for the 1 in 3 patients with CYP3A5 and/or BCRP variant genotypes when prescribed rosuvastatin 10 mg, compared with simvastatin 40 mg. Clinical Trial Registration- URL: http://isrctn.org. Unique identifier: ISRCTN 89508434.
authors.affiliation: Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, United Kingdom.
authors.forename: Kristian M
authors.initials: KM
authors.lastname: Bailey
authors.forename: Simon P R
authors.initials: SP
authors.lastname: Romaine
authors.forename: Beryl M
authors.initials: BM
authors.lastname: Jackson
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Farrin
authors.forename: Maria
authors.initials: M
authors.lastname: Efthymiou
authors.forename: Julian H
authors.initials: JH
authors.lastname: Barth
authors.forename: Joanne
authors.initials: J
authors.lastname: Copeland
authors.forename: Terry
authors.initials: T
authors.lastname: McCormack
authors.forename: Andrew
authors.initials: A
authors.lastname: Whitehead
authors.forename: Marcus D
authors.initials: MD
authors.lastname: Flather
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Jane
authors.initials: J
authors.lastname: Nixon
authors.forename: Alistair S
authors.initials: AS
authors.lastname: Hall
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Balmforth
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000368:Aged; D008078:Cholesterol, LDL / Q000097:blood; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D005260:Female; D005464:Fluorobenzenes / Q000627:therapeutic use*; D005838:Genotype; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D016017:Odds Ratio; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011743:Pyrimidines / Q000627:therapeutic use*; D012044:Regression Analysis; D000068718:Rosuvastatin Calcium; D019821:Simvastatin / Q000627:therapeutic use; D013449:Sulfonamides / Q000627:therapeutic use*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D008078:Cholesterol, LDL; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D011743:Pyrimidines; C503999:SLCO1B1 protein, human; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D003577:Cytochrome P-450 Enzyme System; D019821:Simvastatin; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A