Human Molecular Genetics Advance Access published online on May 11, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi180
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1 Institute of Biomedical Sciences, Academia Sinica, Taiwan
* To whom correspondence should be addressed. Warfarin, a commonly prescribed anticoagulant, exhibited large inter-individual and inter-ethnic differences in the dose required for its anti-coagulation 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 (=1.5 mg/d, n=11) or resistance (=6.0 mg/d, 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 4 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, GG genotypes were comparable in Chinese patients receiving warfarin (79.7%, 17.6%, 2.7%) and normal Chinese controls (82%, 18%, 0%), but differed significantly from Caucasians (14%, 47%, 39%) (p < 0.0001). The promoter polymorphism abolished an E-box consensus sequences and dual luciferase assay revealed that VOKRC1 promoter with the G allele had a 44% increase of activity compared to 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.
Received March 24, 2005
Revised April 28, 2005
Accepted April 28, 2005
Article
A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity
2 Institute of Biomedical Sciences, Academia Sinica, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taiwan
3 Division of Cardiovascular Surgery, Kaohsiung Medical University Hospital, Taiwan
4 Division of Cardiology, Taipei Veterans General Hospital and National Yang-Ming University
5 Department of Cardiovascular Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taiwan
6 Institute of Biomedical Sciences, Academia Sinica, Taiwan; Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, 27710, USA
Yuan-Tsong Chen, E-mail: chen0010{at}ibms.sinica.edu.tw
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