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Previous Volume 352:2285-2293 June 2, 2005 Number 22 Next

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ABSTRACT

Background The management of warfarin therapy is complicated by a wide variation among patients in drug response. Variants in the gene encoding vitamin K epoxide reductase complex 1 (VKORC1) may affect the response to warfarin.

Methods We conducted a retrospective study of European-American patients receiving long-term warfarin maintenance therapy. Multiple linear-regression analysis was used to determine the effect of VKORC1 haplotypes on the warfarin dose. We determined VKORC1 haplotype frequencies in African-American, European-American, and Asian-American populations and VKORC1 messenger RNA (mRNA) expression in human liver samples.

Results We identified 10 common noncoding VKORC1 single-nucleotide polymorphisms and inferred five major haplotypes. We identified a low-dose haplotype group (A) and a high-dose haplotype group (B). The mean (±SE) maintenance dose of warfarin differed significantly among the three haplotype group combinations, at 2.7±0.2 mg per day for A/A, 4.9±0.2 mg per day for A/B, and 6.2±0.3 mg per day for B/B (P<0.001). VKORC1 haplotype groups A and B explained approximately 25 percent of the variance in dose. Asian Americans had a higher proportion of group A haplotypes and African Americans a higher proportion of group B haplotypes. VKORC1 mRNA levels varied according to the haplotype combination.

Conclusions VKORC1 haplotypes can be used to stratify patients into low-, intermediate-, and high-dose warfarin groups and may explain differences in dose requirements among patients of different ancestries. The molecular mechanism of this warfarin dose response appears to be regulated at the transcriptional level.

Source Information

From the Departments of Genome Sciences (M.J.R., D.A.N.), Epidemiology (A.P.R.), Pharmacy (D.K.B., D.L.V.), Pharmaceutics (K.E.T.), and Medicinal Chemistry (A.E.R.), University of Washington, Seattle; and the Departments of Medicine (B.F.G., C.S.E., H.L.M.) and Pathology and Immunology (C.S.E.), Washington University, St. Louis.

Address reprint requests to Dr. Rieder at the Department of Genome Sciences, University of Washington, Box 357730, Seattle, WA 98195, or at mrieder{at}u.washington.edu.

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