title: Genetic variation in the ABCC2 gene is associated with dose decreases or switches to other cholesterol-lowering drugs during simvastatin and atorvastatin therapy.
abstract: Several statins are substrates for the multidrug resistance-associated protein 2 transporter, encoded by the ABCC2 gene. We analyzed in the Rotterdam Study whether the common polymorphisms -24C>T, 1249G>A and 3972C>T in the ABCC2 gene were associated with a dose decrease or switch to another cholesterol-lowering drug in simvastatin and atorvastatin users. These events could indicate an adverse effect or a too strong reduction in cholesterol level. We identified 1014 simvastatin and atorvastatin users during the period 1 January 1991 to 1 January 2010. Associations between genetic variation and the risk of these events were analyzed using Cox proportional hazards modelling. The ABCC2 -24C>T genotype (HR 1.32 95% CI 1.04-1.69) and the H12 haplotype versus the H2 haplotype (HR 1.49; 95% CI 1.06-2.09) were associated with these events in simvastatin users. A similar but not significant association was found in atorvastatin users. To conclude, genetic variation in the ABCC2 gene is associated with these events in simvastatin users.
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: M L
authors.initials: ML
authors.lastname: Becker
authors.forename: L L F S
authors.initials: LL
authors.lastname: Elens
authors.forename: L E
authors.initials: LE
authors.lastname: Visser
authors.forename: A
authors.initials: A
authors.lastname: Hofman
authors.forename: A G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: R H N
authors.initials: RH
authors.lastname: van Schaik
authors.forename: B H
authors.initials: BH
authors.lastname: Stricker
mesh_terms: D000368:Aged; D000924:Anticholesteremic Agents / Q000008:administration & dosage; D000069059:Atorvastatin; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006239:Haplotypes; D006538:Heptanoic Acids / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011758:Pyrroles / Q000008:administration & dosage*; D019821:Simvastatin / Q000008:administration & dosage*
chemical_list: D000924:Anticholesteremic Agents; D000069059:Atorvastatin; D002784:Cholesterol; D006538:Heptanoic Acids; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011758:Pyrroles; D019821:Simvastatin; C000715087:ABCC2 protein, human