Interethnic variability of warfarin maintenance requirement is explained by VKORC1 genotype in an Asian population.

BACKGROUND: Chinese and Malay subjects have been reported to require less maintenance warfarin than Indians that could not be accounted for by cytochrome P450 (CYP) 2C9 variants. Vitamin K epoxide reductase complex 1 (VKORC1) is the target enzyme of warfarin, and VKORC1 intronic variants and haplotypes have recently been shown to influence VKORC1 activity and warfarin requirements. METHODS: We sequenced the coding regions of CYP2C9 and VKORC1 and inferred VKORC1 haplotype from 10 intronic variants in 147 Chinese, 85 Malay, and 43 Indian patients receiving maintenance warfarin. RESULTS: The mean weight-normalized warfarin dose was lower for Chinese and Malays than for Indians (0.058 +/- 0.025 mg/kg, 0.059 +/- 0.023 mg/kg, and 0.089 +/- 0.036 mg/kg, respectively; P < .001 for comparisons between Chinese and Malays with Indians). CYP2C9*2 and VKORC1 coding region variants were rare (<2%), whereas CYP2C9*3 associated with lower warfarin requirements was less common in Chinese and Malays (7% and 9%, respectively) than in Indians (18%) and could not account for their lower warfarin requirements. VKORC1 H1 and H7/H8/H9 haplotypes were associated with lower and higher warfarin requirements, respectively (0.050 +/- 0.019 mg/kg and 0.092 +/- 0.057 mg/kg, respectively; P < .001). VKORC1 H1 haplotype (requiring low warfarin doses) was common in Chinese (87%) and Malays (65%) but uncommon in Indians (12%), whereas H7, H8, and H9 haplotypes (requiring high warfarin doses) were rare in Chinese (9%), intermediate in Malays (30%), and common in Indians (82%). The interethnic difference in warfarin requirements became nonsignificant when adjusted for VKORC1 haplotype. CONCLUSIONS: Interethnic difference in VKORC1 haplotypes accounts for the difference in warfarin requirements between Chinese, Malays, and Indians, providing interesting insights into genetic variation between ethnogeographically distinct Asian groups.

Novel CYP2C9 genetic variants in Asian subjects and their influence on maintenance warfarin dose.

BACKGROUND: Commonly occurring genetic variants in CYP2C9 are known to reduce catalytic activity and are associated with enhanced patient sensitivity to warfarin. Interethnic differences in warfarin dose requirement have been described in the Asian population, and we postulate that this could be related to genetic variants of CYP2C9 that are unique to ethnic groups. METHODS: We prospectively genotyped 125 patients who were receiving a stable daily warfarin dose to maintain international normalized ratio values between 2 and 3 through comprehensive sequencing of the promoter and coding regions of the CYP2C9 gene. RESULTS: The mean weight-adjusted warfarin maintenance dose was significantly lower for Malay and Chinese subjects than Indian subjects ( P <.001 and.014, respectively). Warfarin dose negatively correlated with age (r = -0.4, P <.001) but not with sex. Multiple variants were detected in the promoter, exonic, intronic, and 3'-untranslated regions of CYP2C9, of which 16 were novel, including 7 nonsynonymous exonic variants ( 208G>C, 374G>A, 485C>A, 895A>G, 1144C>T, 1190A>C, and 1362G>C ). CYP2C9*3, but not CYP2C9*2, was found in Chinese and Malay patients, and carriers of the CYP2C9*3 variant in Chinese ( P <.01) and Indian ( P <.01) patients, but not Malay patients ( P =.77), required less warfarin. The influence of the novel exonic variants on warfarin dose requirement was unclear, because they were rare, but the lower warfarin dose requirement for Chinese and Malay patients existed despite omission of individuals with any coding region variants from analysis. CONCLUSIONS: Interethnic differences in warfarin dosing in Asian subjects may result from other genetic, dietary, or environmental influences; however, these novel variants in the gene warrant further characterization through functional studies.