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A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity.

Publication ,  Journal Article
Yuan, H-Y; Chen, J-J; Lee, MTM; 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
Published in: Hum Mol Genet
July 1, 2005

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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Published In

Hum Mol Genet

DOI

ISSN

0964-6906

Publication Date

July 1, 2005

Volume

14

Issue

13

Start / End Page

1745 / 1751

Location

England

Related Subject Headings

  • White People
  • Warfarin
  • Vitamin K Epoxide Reductases
  • Promoter Regions, Genetic
  • Polymorphism, Single Nucleotide
  • Mixed Function Oxygenases
  • Middle Aged
  • Male
  • Humans
  • Genotype
 

Citation

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Yuan, H.-Y., Chen, J.-J., Lee, M. T. M., Wung, J.-C., Chen, Y.-F., Charng, M.-J., … Chen, Y.-T. (2005). A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet, 14(13), 1745–1751. https://doi.org/10.1093/hmg/ddi180
Yuan, Hsiang-Yu, Jin-Jer Chen, MT Michael Lee, Ju-Chieh Wung, Ying-Fu Chen, Min-Ji Charng, Ming-Jen Lu, et al. “A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity.Hum Mol Genet 14, no. 13 (July 1, 2005): 1745–51. https://doi.org/10.1093/hmg/ddi180.
Yuan H-Y, Chen J-J, Lee MTM, Wung J-C, Chen Y-F, Charng M-J, et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet. 2005 Jul 1;14(13):1745–51.
Yuan, Hsiang-Yu, et al. “A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity.Hum Mol Genet, vol. 14, no. 13, July 2005, pp. 1745–51. Pubmed, doi:10.1093/hmg/ddi180.
Yuan H-Y, Chen J-J, Lee MTM, 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. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet. 2005 Jul 1;14(13):1745–1751.
Journal cover image

Published In

Hum Mol Genet

DOI

ISSN

0964-6906

Publication Date

July 1, 2005

Volume

14

Issue

13

Start / End Page

1745 / 1751

Location

England

Related Subject Headings

  • White People
  • Warfarin
  • Vitamin K Epoxide Reductases
  • Promoter Regions, Genetic
  • Polymorphism, Single Nucleotide
  • Mixed Function Oxygenases
  • Middle Aged
  • Male
  • Humans
  • Genotype