title: CYP2C9 and ABCG2 polymorphisms as risk factors for developing adverse drug reactions in renal transplant patients taking fluvastatin: a case-control study.
abstract: OBJECTIVE
  To investigate whether an association exists between fluvastatin-induced adverse drug reactions (ADRs) and polymorphisms in genes encoding the metabolizing enzyme CYP2C9 and the drug transporter ABCG2 in renal transplant recipients (RTRs).
  
  
  METHODS
  Fifty-two RTRs that experienced fluvastatin ADRs and 52 controls matched for age, gender, dose of fluvastatin and immunosuppressive use were enrolled in the study. Genotyping for CYP2C9*2, *3 and ABCG2 421C>A variants was performed by real-time PCR.
  
  
  RESULTS
  CYP2C9 homozygous and heterozygous mutant allele (*2 or *3) carriers had 2.5-times greater odds of developing adverse effects (χ² = 4.370; degrees of freedom = 1; p = 0.037; φ = 0.21, odds ratio [OR]: 2.44; 95% CI: 1.05-5.71). Patients who were the carriers of at least one mutant CYP2C9 allele (*2 or *3) and who were receiving CYP2C9 inhibitors, had more than six-times greater odds of having adverse effects than those without the inhibitor included in their therapy (p = 0.027; OR: 6.59; 95% CI: 1.24-35.08). Patients with ABCG2 421CA or AA (taken together) had almost four-times greater odds of developing adverse effects than those with ABCG2 421CC genotype (χ² = 6.190; degrees of freedom = 1; p = 0.013; φ = 0.24, OR: 3.81; 95% CI: 1.27-11.45). Patients with A allele had 2.75-times (95% CI: 1.02-7.40) greater odds of developing adverse effects than those with C allele.
  
  
  CONCLUSIONS
  Our preliminary data demonstrate an association between fluvastatin-induced ADRs in RTRs and genetic variants in the CYP2C9 and ABCG2 genes.
authors.affiliation: Pharmacovigilance Unit, Agency for Medicinal Products & Medical Devices, Ksaverska Cesta 4, 10000 Zagreb, Croatia.
authors.forename: Nikica
authors.initials: N
authors.lastname: Miroševic Skvrce
authors.forename: Nada
authors.initials: N
authors.lastname: Božina
authors.forename: Lada
authors.initials: L
authors.lastname: Zibar
authors.forename: Ivan
authors.initials: I
authors.lastname: Barišic
authors.forename: Lana
authors.initials: L
authors.lastname: Pejnovic
authors.forename: Viola
authors.initials: V
authors.lastname: Macolic Šarinic
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D016022:Case-Control Studies; D065729:Cytochrome P-450 CYP2C9; D064420:Drug-Related Side Effects and Adverse Reactions; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D000077340:Fluvastatin; D056726:Genetic Association Studies; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D009363:Neoplasm Proteins; D000077340:Fluvastatin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases