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A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity
Abstract
Warfarin, a commonly prescribed anticoagulant, exhibited large inter-individual and inter-ethnic differences in the dose required for its anticoagulation effect. Asian populations, including Chinese, require a much lower maintenance dose than Caucasians, for which the mechanisms still remain unknown. We determined DNA sequence variants in CYP2C9 and VKORC1 in 16 Chinese patients having warfarin sensitivity (< or = 1.5 mg/day, n = 11) or resistance (> or = 6.0 mg/day, n = 5), 104 randomly selected Chinese patients receiving warfarin, 95 normal Chinese controls and 92 normal Caucasians. We identified three CYP2C9 variants, CYP2C9*3, T299A and P382L, in four warfarin-sensitive patients. A novel VKORC1 promoter polymorphism (-1639 G > A) presented in the homozygous form (genotype AA) was found in all warfarin-sensitive patients. The resistant patients were either AG or GG. Among the 104 randomly selected Chinese patients receiving warfarin, AA genotype also had lower dose than the AG/GG genotype (P < 0.0001). Frequencies of AA, AG and GG genotypes were comparable in Chinese patients receiving warfarin (79.7, 17.6 and 2.7%) and normal Chinese controls (82, 18 and 0%), but differed significantly from Caucasians (14, 47 and 39%) (P < 0.0001). The promoter polymorphism abolished the E-box consensus sequences and dual luciferase assay revealed that VOKRC1 promoter with the G allele had a 44% increase of activity when compared with the A allele. The differences in allele frequencies of A/G allele and its levels of VKORC1 promoter activity may underscore the inter-individual differences in warfarin dosage as well as inter-ethnic differences between Chinese and Caucasians.
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Cited by
Clinical assessment incorporating a personal genome
Ashley, E. A., Butte, A. J., Wheeler, M. T., Chen, R., Klein, T. E., Dewey, F. E., Dudley, J. T., Ormond, K. E., Pavlovic, A., Morgan, A. A., et al. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60452-7 · Cited by 674
Takahashi, H., Wilkinson, G. R., Nutescu, E. A., Morita, T., Ritchie, M. D., Scordo, M. G., Pengo, V., Barban, M., Padrini, R., Ieiri, I., et al. (2006) · Pharmacogenetics and Genomics · doi:10.1097/01.fpc.0000184955.08453.a8 · Cited by 376
AQUILANTE, C., LANGAEE, T., LOPEZ, L., YARANDI, H., TROMBERG, J., MOHUCZY, D., GASTON, K., WADDELL, C., CHIRICO, M., & JOHNSON, J. (2006) · Clinical Pharmacology & Therapeutics · doi:10.1016/j.clpt.2005.11.011 · Cited by 266
Metadata
- Authors
- Yuan, H.-Y., Chen, J.-J., Lee, M. T. M., Wung, J.-C., Chen, Y.-F., Charng, M.-J., Lu, M.-J., Hung, C.-R., Wei, C.-Y., Chen, C.-H., Wu, J.-Y., & Chen, Y.-T.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-05-11
- Volume
- 14
- Issue
- 13
- Pages
- 1745-1751
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2102553995
- Cited by
- 486
- References
- 0
- FWCI
- 27.91
- Type
- journal article
- Language
- en
- Open access
- closed
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- Yuan, H.-Y., Chen, J.-J., Lee, M. T. M., Wung, J.-C., Chen, Y.-F., Charng, M.-J., Lu, M.-J., Hung, C.-R., Wei, C.-Y., Chen, C.-H., Wu, J.-Y., & Chen, Y.-T. (2005). A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Human Molecular Genetics. https://doi.org/10.1093/hmg/ddi180
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