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- Title
Interethnic variability of warfarin maintenance requirement is explained by VKORC1 genotype in an Asian population<sup>*</sup>.
- Authors
Soo-Chin Lee; Swee-Siang Ng; Oldenburg, Johannes; Pei-Yi Chong; Rost, Simone; Jia-Yi Guo; Hui-Ling Yap; Rankin, Sheila Clare; Hui-Boon Khor; Tiong-Cheng Yeo; Kheng-Siang Ng; Richie Soong; Boon-Cher Goh
- Abstract
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.Clinical Pharmacology & Therapeutics (2006) 79, 197–205; doi: 10.1016/j.clpt.2005.11.006
- Subjects
CLINICAL pharmacology; WARFARIN; CYTOCHROME P-450; VITAMIN K; CHINESE people; MALAYSIANS; INDIGENOUS peoples of the Americas
- Publication
Clinical Pharmacology & Therapeutics, 2006, Vol 79, Issue 3, p197
- ISSN
0009-9236
- Publication type
Article
- DOI
10.1016/j.clpt.2005.11.006