Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.
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.
Rieder
Mark J
MJ
Department of Genome Sciences, University of Washington, Seattle, USA.
Reiner
Alexander P
AP
Gage
Brian F
BF
Nickerson
Deborah A
DA
Eby
Charles S
CS
McLeod
Howard L
HL
Blough
David K
DK
Thummel
Kenneth E
KE
Veenstra
David L
DL
Rettie
Allan E
AE
D000925:Anticoagulants / Q000008:administration & dosage*; D004247:DNA / Q000032:analysis; D005786:Gene Expression Regulation; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D016014:Linear Models; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D012189:Retrospective Studies; D014158:Transcription, Genetic; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage*
D000925:Anticoagulants; D012333:RNA, Messenger; D014859:Warfarin; D004247:DNA; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases