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Human Molecular Genetics Advance Access originally published online on May 11, 2005
Human Molecular Genetics 2005 14(13):1745-1751; doi:10.1093/hmg/ddi180
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

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

Hsiang-Yu Yuan1, Jin-Jer Chen1,2, M.T. Michael Lee1, Ju-Chieh Wung1, Ying-Fu Chen3, Min-Ji Charng4, Ming-Jen Lu5, Chi-Ren Hung5, Chun-Yu Wei1, Chien-Hsiun Chen1, Jer-Yuarn Wu1 and Yuan-Tsong Chen1,6,*

1Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, 2Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, 3Division of Cardiovascular Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, 4Division of Cardiology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan, 5Department of Cardiovascular Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan and 6Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA

* To whom correspondence should be addressed at: Institute of Biomedical Sciences, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei, Taiwan. Tel: +886 227899104; Fax: +886 227825573; Email: chen0010{at}ibms.sinica.edu.tw

Received March 24, 2005; Accepted May 2, 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 (≤1.5 mg/day, n=11) or resistance (≥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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