Distribution of CYP2C9 and VKORC1 risk alleles for warfarin sensitivity and resistance in the Israeli population.
OBJECTIVE
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 approximately 95% of Jews, approximately 84% of Druze and approximately 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.
Efrati
Edna
E
Center for Translational Genetics, B. Rappaport Institute for Research in Medical Sciences, Faculty of Medicine, Technion-Israel Institute of Technology and Rambam Health Care Campus, Haifa, Israel.
Elkin
Hela
H
Sprecher
Eli
E
Krivoy
Norberto
N
D000483:Alleles; D000925:Anticoagulants / Q000494:pharmacology*; D018912:Arabs / Q000235:genetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D004351:Drug Resistance / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007514:Islam; D007557:Israel; D007585:Jews / Q000235:genetics; D006899:Mixed Function Oxygenases / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000494:pharmacology*
D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases