title: The SLCO1B1 c.521T>C polymorphism is associated with dose decrease or switching during statin therapy in the Rotterdam Study.
abstract: OBJECTIVE
  The SLCO1B1 c.521T>C polymorphism is associated with statin plasma levels and simvastatin-induced adverse drug reactions. We studied whether the c.521T>C polymorphism is associated with dose decreases or switches to other cholesterol-lowering drugs during simvastatin and atorvastatin therapy, because these events are indicators of adverse drug reactions.
  
  
  METHODS
  We identified 1939 incident simvastatin and atorvastatin users in the Rotterdam Study, a population-based cohort study. Associations were studied using Cox proportional hazards analysis. Meta-analysis was performed with data from the Utrecht Cardiovascular Pharmacogenetics study.
  
  
  RESULTS
  Simvastatin users with the c.521 CC genotype had a significantly higher risk of a dose decrease or switch than users with the TT genotype [hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.05-2.88]. Female sex, age below 70 years, and low starting dose were risk factors. In atorvastatin users with starting dose of more than 20 mg, the risk of a dose decrease or switch was higher in users carrying a C allele than in users with the TT genotype (HR 3.26, 95% CI 1.47-7.25). In the meta-analysis the association in simvastatin users remained, with a significantly higher risk of a dose decrease or switch in simvastatin users with two minor alleles (HR 1.69, 95% CI 1.05-2.73). For atorvastatin users no significant association was found.
  
  
  CONCLUSIONS
  In simvastatin users in the Rotterdam Study, we demonstrated an association between the c.521T>C polymorphism and dose decrease or switching, as indicators of adverse drug reactions, and provided risk factors for this association. For atorvastatin, an association was found in users with a starting dose of more than 20 mg.
authors.affiliation: Departments of aEpidemiology bInternal Medicine, Erasmus Medical Center, Rotterdam cDrug Safety Unit, The Health Care Inspectorate dDepartment of Hospital Pharmacy, Pharmacy Foundation of The Hague Hospitals - HAGA eNetherlands Consortium of Healthy Aging, The Hague fDepartment of Pharmacoepidemiology & Clinical Pharmacotherapy, Utrecht University, Utrecht gDepartment of Clinical Pharmacy, St Antonius Hospital Nieuwegein, Nieuwegein hDepartment of Hospital Pharmacy, Pharmacy Foundation of Haarlem Hospitals, Haarlem, The Netherlands iDepartment of Molecular Genetics, Pharmacogenetics and Hormone Research, Bicêtre Hospital, Paris, France.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: de Keyser
authors.forename: Bas J M
authors.initials: BJ
authors.lastname: Peters
authors.forename: Matthijs L
authors.initials: ML
authors.lastname: Becker
authors.forename: Loes E
authors.initials: LE
authors.lastname: Visser
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Olaf H
authors.initials: OH
authors.lastname: Klungel
authors.forename: Céline
authors.initials: C
authors.lastname: Verstuyft
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Anke-Hilse
authors.initials: AH
authors.lastname: Maitland-van der Zee
authors.forename: Bruno H
authors.initials: BH
authors.lastname: Stricker
mesh_terms: D000368:Aged; D000375:Aging; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000069059:Atorvastatin; D002784:Cholesterol / Q000378:metabolism; D003596:Cytosine; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D005260:Female; D056726:Genetic Association Studies; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000235:genetics; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012307:Risk Factors; D012727:Sex Characteristics; D019821:Simvastatin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013941:Thymine
chemical_list: D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D011758:Pyrroles; C503999:SLCO1B1 protein, human; D003596:Cytosine; D002784:Cholesterol; D000069059:Atorvastatin; D019821:Simvastatin; D013941:Thymine