title: Genetic polymorphisms in warfarin and tacrolimus-related genes VKORC1, CYP2C9 and CYP3A5 in the Greek-Cypriot population.
abstract: BACKGROUND
  Two variants in the gene encoding the cytochrome P450 2C9 enzyme (CYP2C9) are considered the most significant genetic risk factors associated with bleeding after warfarin prescription. A variant in the vitamin K epoxide reductase (VKORC1) has been also associated by several studies with warfarin response. Another variant in the P450 3A5 enzyme (CYP3A5) gene is known to affect the metabolism of many drugs, including tacrolimus.
  
  
  RESULTS
  We conducted a population genetic study in 148 unrelated healthy Greek-Cypriot volunteers (through PCR-RFLP assays), in order to determine the frequencies of the above pharmacogenetics variants and to compare allele frequencies with those in other major ethnic groups. The allele frequencies of CYP2C9*2, CYP2C9*3 and CYP3A5*3 were found to be 0.162, 0.112 and 0.943 respectively, whereas VKORC1 - 1639A was 0.534. The latter frequency differs significantly when compared with Caucasians, Asians and Africans (p < 0.001) and is still significant when compared with the geographically and culturally closely related to Greek-Cypriots, Hellenes of Greece (p = 0.01). Interestingly ~18% of our population are carriers of four or three risk alleles regarding warfarin sensitivity, therefore they have a high predisposition for bleeding after taking high or even normal warfarin doses.
  
  
  CONCLUSIONS
  Our data show no significant difference in the frequency of CYP2C9 and CYP3A5 allelic variants when compared to the Caucasian population, but differ significantly when compared with Africans and Asians (p < 0.001). Also, the frequency of variant VKORC1 - 1639A differs between Greek-Cypriots and every other population we compared. Finally, about 1/5 Greek-Cypriots carry three or four risk alleles and ~50% of them carry at least two independent risk alleles regarding warfarin sensitivity, a potentially high risk for over-anticoagulation.
authors.forename: Despina
authors.initials: D
authors.lastname: Hadjipanagi
authors.forename: Stephanie
authors.initials: S
authors.lastname: Chrysanthou
authors.affiliation: Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus. kvoskar@ucy.ac.cy.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Voskarides
authors.forename: Constantinos
authors.initials: C
authors.lastname: Deltas
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D003535:Cyprus; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000209:etiology / Q000235:genetics*; D005838:Genotype; D006115:Greece / Q000208:ethnology; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D012307:Risk Factors; D016559:Tacrolimus / Q000008:administration & dosage; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*; D014859:Warfarin / Q000009:adverse effects; D055815:Young Adult
chemical_list: D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D016559:Tacrolimus