Warfarin Pharmacogenetics: CYP2C9 and VKORC1 Genotypes Predict Different Sensitivity and Resistance Frequencies in the Ashkenazi and Sephardi Jewish Populations

Warfarin is a widely used anticoagulant that has a narrow therapeutic range because of both genetic and environmental factors. CYP2C9^*2 (p.R144C), CYP2C9^*3 (p.I359L), and the VKORC1 promoter (g.-1639G→A) polymorphisms occur frequently in patients who are warfarin "sensitive" and require lower doses, whereas patients with VKORC1 missense mutations are warfarin "resistant" and require higher doses. To compare the CYP2C9 and VKORC1 allele and genotype frequencies among 260 Ashkenazi (AJ) and 80 Sephardi Jewish (SJ) individuals, we genotyped six CYP2C9 and eight VKORC1 alleles by using the Tag-It Mutation Detection Kit and PCR-RFLP assays. The "sensitive" CYP2C9^*2 and ^*3 alleles had significantly higher frequencies in SJ than in AJ individuals, 0.194 and 0.144 versus 0.127 and 0.081, respectively (p ≤ 0.001). In contrast, the VKORC1 p.D36Y mutation, which predicts warfarin "resistance," had a significantly higher frequency in AJ than in SJ individuals, 0.043 versus 0.006, respectively (p ≤ 0.025). Of note, 11.3% of AJ individuals predicted to be CYP2C9 extensive metabolizers and 8.7% of those predicted to be intermediate and poor metabolizers were VKORC1 p.D36Y carriers who require markedly higher warfarin doses. Thus, ∼10% of all AJ individuals would be misclassified when only genotyping CYP2C9^*2, ^*3, and VKORC1 g.-1639G→A, underscoring the importance of screening for p.D36Y prior to initiating warfarin anticoagulation in AJ individuals. Taken together, our findings show that ∼85% of AJ and ∼90% of SJ individuals have at least one "sensitive" (CYP2C9^*2, ^*3, VKORC1 g.-1639G→A) or "resistant" (VKORC1 p.D36Y) allele, indicating that each group has different warfarin pharmacogenetics and would benefit from genotype-based dose predictions.