Distribution of CYP2C9 and VKORC1 Risk Alleles for Warfarin Sensitivity and Resistance in the Israeli Population
Edna Efrati, Hela Elkin, Eli Sprecher and Norberto Krivoy
Affiliation: Clinical Pharmacology Institute, Rambam Health Care Campus and Faculty of Medicine, Technion–Haifa, Israel.
Purpose: This study was designed to delineate the relative frequency of CYP2C9 and VKORC1 polymorphisms known to affect warfarin response in the highly heterogeneous Israeli population. Methods: Frequencies of CYP2C9 allelic variants CYP2C9*2, CYP2C9*3 and of VKORC1 single nucleotide polymorphisms (snps)- 1639G > A and D36Y were determined in genomic DNA of 438 healthy unrelated Israeli volunteers of Jewish, Druze and Arab Moslem descent, using allele specific PCR-RFLP. Genotyping results obtained were confirmed by probe free High Resolution Melt (HRM) Technology. Results: Arab Moslems had a higher frequency of warfarin “sensitive” CYP2C9*2, CYP2C9*3 and VKROC1-1639G > A alleles (0.21, 0.07 and 0.58, respectively) than both Jews (0.13, 0.11 and 0.57, respectively) and Druze (0.12, 0.06 and 0.53, respectively). Statistically significant differences were found in CYP2C9*2 between Druze and Moslems (p=0.01) and between Jews and Moslems (p=0.016) and in CYP2C9*3 between Druze and Jews (p=0.0086). VKORC1(-1639G > A) was the major gene polymorphism associated with warfarin sensitivity in all 3 subpopulations. In contrast, the warfarin “resistant” VKORC1 D36Y allele was very rare in the Israeli population (0- 0.015). The results presented demonstrate that allelic variants in CYP2C9 and VKORC1 are very common in Israel with ∼95% of Jews, ∼84% of Druze and ∼91% of Arab Moslems manifesting at least one known warfarin “sensitive” or “resistant” allele. Conclusions: Individualized genotype based warfarin therapy is highly relevant in the Israeli population due to the high incidence of genetic variations associated with warfarin sensitivity in all 3 non-mixing subpopulations tested.
Keywords: Warfarin, CYP2C9, VKORC1, single nucleotide polymorphism, pharmacogenetics, HRM
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