Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose

被引:1048
作者
Rieder, MJ
Reiner, AP
Gage, BF
Nickerson, DA
Eby, CS
McLeod, HL
Blough, DK
Thummel, KE
Veenstra, DL
Rettie, AE
机构
[1] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA
[2] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA
[3] Univ Washington, Dept Pharm, Seattle, WA 98195 USA
[4] Univ Washington, Dept Pharmaceut, Seattle, WA 98195 USA
[5] Univ Washington, Dept Med Chem, Seattle, WA 98195 USA
[6] Washington Univ, Dept Med, St Louis, MO USA
[7] Washington Univ, Dept Pathol & Immunol, St Louis, MO USA
关键词
D O I
10.1056/NEJMoa044503
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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页码:2285 / 2293
页数:9
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