title: The SLCO1B1*5 genetic variant is associated with statin-induced side effects.
abstract: OBJECTIVE
  We sought to identify single nucleotide polymorphisms associated with mild statin-induced side effects.
  
  
  BACKGROUND
  Statin-induced side effects can interfere with therapy. Single nucleotide polymorphisms in cytochrome P450 enzymes impair statin metabolism; the reduced function SLCO1B1*5 allele impairs statin clearance and is associated with simvastatin-induced myopathy with creatine kinase (CK) elevation.
  
  
  METHODS
  The STRENGTH (Statin Response Examined by Genetic Haplotype Markers) study was a pharmacogenetics study of statin efficacy and safety. Subjects (n = 509) were randomized to atorvastatin 10 mg, simvastatin 20 mg, or pravastatin 10 mg followed by 80 mg, 80 mg, and 40 mg, respectively. We defined a composite adverse event (CAE) as discontinuation for any side effect, myalgia, or CK >3x upper limit of normal during follow-up. We sequenced CYP2D6, CYP2C8, CYP2C9, CYP3A4, and SLCO1B1 and tested 7 reduced function alleles for association with the CAE.
  
  
  RESULTS
  The CAE occurred in 99 subjects (54 discontinuations, 49 myalgias, and 9 CK elevations). Sex was associated with CAE (percent female in CAE vs. no CAE groups, 66% vs. 50%, p < 0.01). SLCO1B1*5 was associated with CAE (percent with > or = 1 allele in CAE vs. no CAE groups, 37% vs. 25%, p = 0.03) and those with CAE with no significant CK elevation (p < or = 0.03). Furthermore, there was evidence for a gene-dose effect (percent with CAE in those with 0, 1, or 2 alleles: 19%, 27%, and 50%, trend p = 0.01). Finally, the CAE risk appeared to be greatest in those carriers assigned to simvastatin.
  
  
  CONCLUSIONS
  SLCO1B1*5 genotype and female sex were associated mild statin-induced side effects. These findings expand the results of a recent genome-wide association study of statin myopathy with CK >3x normal to milder, statin-induced, muscle side effects.
authors.affiliation: Division of Cardiovascular Medicine, Duke University Medical Center, Durham, North Carolina 27708, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Voora
authors.forename: Svati H
authors.initials: SH
authors.lastname: Shah
authors.forename: Ivan
authors.initials: I
authors.lastname: Spasojevic
authors.forename: Shazia
authors.initials: S
authors.lastname: Ali
authors.forename: Carol R
authors.initials: CR
authors.lastname: Reed
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Salisbury
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Ginsburg
mesh_terms: D000368:Aged; D000069059:Atorvastatin; D003402:Creatine Kinase / Q000097:blood; D005260:Female; D006239:Haplotypes; D006538:Heptanoic Acids / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics; D000960:Hypolipidemic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D009135:Muscular Diseases / Q000097:blood / Q000139:chemically induced*; D027361:Organic Anion Transporters / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017035:Pravastatin / Q000009:adverse effects / Q000493:pharmacokinetics; D011758:Pyrroles / Q000009:adverse effects / Q000493:pharmacokinetics; D019821:Simvastatin / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D011758:Pyrroles; C503999:SLCO1B1 protein, human; D000069059:Atorvastatin; D019821:Simvastatin; D003402:Creatine Kinase; D017035:Pravastatin