title: Association between the CYP2C9 polymorphism and the drug metabolism phenotype.
abstract: CYP2C9, an isoform of the cytochrome P450 enzyme, is involved in the metabolism of most of the drugs of choice for the treatment of thromboembolic disorders. Functional polymorphism is associated with two variant alleles (alleles *2 and *3) encoding CYP2C9 enzymes with a potentially different catalytic activity. The aim of the study was to determine the frequency of the CYP2C9 polymorphism in a representative sample of the Croatian population (n = 177) and to assess the association between the CYP2C9 polymorphism and the warfarin dose in patients with thromboembolism (n = 181). The CYP2C9 genotype was determined by polymerase chain reaction-restriction fragment length poymorphism (PCR-RFLP). According to the CYP2C9 genotype distribution, 31.2% of the healthy subjects were identified with a heterozygous or homozygous CYP2C9 variant genotype. The frequency of 2C9*2 and 2C9*3 alleles was 12.4% and 3.7%, respectively. There was no gender-related genotype or allele difference. In thromboembolism patients, the frequency of CYP2C9 alleles *2 and *3 was 17.4% and 6.6%, respectively, and did not differ significantly from the control group. Almost half (42.5%) of the patients carried at least one variant CYP2C9 genotype. The allele difference between patient subgroups receiving warfarin doses lower and higher than the optimal warfarin dose (4.1 mg/day) was significant (p = 0.027), especially for allele 2C9*3 (p = 0.019; OR 3.250, 95%, CI 1.263-8.413). Comparison of the warfarin dose between patients with different genotypes yielded a significant dose difference between the patients with wild-type genotype and those with variant genotypes (Kruskall-Wallis, chi2 = 9.745, p = 0.008). The results of the association of each of five genotype combinations with the warfarin maintenance dose revealed it to be significantly related to the genotype (Kruskall-Wallis, chi2 = 12.854, p = 0.025). Expressed as percentage of the mean dose in patients with wild-type alleles, the mean warfarin maintenance dose was 92% in 2C9*2 heterozygotes, 74% in 2C*3 heterozygotes, 61% in 2C9*2 homozygotes, 34% in 2C9*3 homozygotes and 63% in compound heterozygotes for 2C9*2 and 2C9*3. Although the mean maintenance dose in homozygous *2/*2 and compound *2/*3 genotype patients was markedly lower (mean 2.66 mg and 2.75 mg, respectively, vs. 4.37 mg), statistical analysis yielded no significance because of the small number of patients carrying these genotypes. A significantly lower maintenance dose was observed in the subgroup of heterozygous *1/*3 genotype patients (p = 0.022). These preliminary results suggest a significant association of the CYP2C9 polymorphism with the warfarin dose and underline the importance of pre-therapeutic genotyping to identify the subjects likely to develop undesirable drug effects.
authors.affiliation: Clinical Institute of Chemistry, School of Medicine, Sestre milosrdnice University Hospital, Zagreb, Croatia. elizabeta.topic@zg.htnet.hr
authors.forename: Elizabeta
authors.initials: E
authors.lastname: Topić
authors.forename: Mario
authors.initials: M
authors.lastname: Stefanović
authors.forename: Marina
authors.initials: M
authors.lastname: Samardzija
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D017523:Croatia; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D013923:Thromboembolism / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D014859:Warfarin / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases