Genetic polymorphisms in warfarin and tacrolimus-related genes VKORC1, CYP2C9 and CYP3A5 in the Greek-Cypriot population

Abstract

BackgroundTwo 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.FindingsWe 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.ConclusionsOur 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.

The allele frequency of CYP2C9 and VKORC1 in the Southern Khorasan population

“…Nonetheless, the prevalence of CYP2C9*2 allele in this population is more than *3 allele, contrary to Birjand population. Similar to Mazandaran and Shiraz population, Cyprus population has a higher frequency of - 1639 A of VKORC1 , all more than that of Birjand population ( 38 ).…”

“…As a result, because of the frequency of polymorphisms in -1639 G>A region of VKORC1 gene, our population is similar to many far populations and different from closer populations. Genotype -1639 AA in Birjand population has the frequency of 12.4% which is different from Mazandaran with 86.2% ( 36 ), Shiraz 55.6% ( 15 ), northwestern of Iran 21% ( 37 ), Chinese 69% ( 40 ), Cyprus 53% ( 38 ), and Argentina populations 20% ( 41 ). But it bears close similarity to Slovak population with 12% ( 3 ) and England with 14.5% frequencies ( 39 ).…”

Genophenotypic Factors and Pharmacogenomics in Adverse Drug Reactions

“…CYP2C9 and VKORC1 variants involved in warfarin PGx show important differences in Greek-Cypriots and Hellenes of Greece as compared to Caucasians, Asians and Africans. Approximately 18% of the Greek-Cypriots are carriers of more than three risk alleles, and approximately 50% of the members of this population are carriers of at least two independent risk alleles associated with warfarin sensitivity, with potential high risk for bleeding at conventional doses of anticoagulants [84]. In the Croatian population, CYP2C9, CYP2C19 and CYP2D6 variants show frequencies similar to other European population with intermediate values between mid-Europeans and Mediterranean populations [85].…”