|
|
Blood, 15 March 2007, Vol. 109, No. 6, pp. 2477-2480.
Prepublished online as a Blood First Edition Paper on November 16, 2006; DOI 10.1182/blood-2006-08-038984.
 Previous Article | Table of Contents | Next Article 
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Brief report
A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance
Ronen Loebstein1,
Ilana Dvoskin2,
Hillel Halkin1,
Manuela Vecsler2,
Aharon Lubetsky1,
Gideon Rechavi3,
Ninette Amariglio3,
Yoram Cohen3,4,
Gie Ken-Dror5,
Shlomo Almog1, and
Eva Gak2
1 Institute of Clinical Pharmacology and Toxicology,
2 Institute of Human Genetics,
3 Cancer Research Center, and
4 Department of Gynecologic Oncology, Sheba Medical Center, Tel Hashomer, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Israel;
5 Department of Epidemiology and Preventive Medicine, Sackler School of Medicine, Tel Aviv University, Israel
CYP2C9 and VKORC1 genetic variants are associated with low and intermediate warfarin dose requirements, but markers of high doses are less well characterized. We analyzed the VKORC1 coding sequence and known CYP2C9 and VKORC1 polymorphisms in 15 selected warfarin-resistant (dose, 80 to 185 mg/wk) and 8 warfarin-sensitive patients (7 to 13 mg/wk) and 99 unselected controls (8 to 105 mg/wk). We identified a coding VKORC1 Asp36Tyr polymorphism in 7 of 15 resistant compared with 0 of 8 sensitive patients (P = .026) Carriers of Asp36Tyr in the control group (8 of 99) required significantly higher warfarin doses of 80.9 ± 10.1 mg/wk compared with 42.7 ± 7.5 mg/wk in noncarriers (F = 9.79, P = .002). Asp36Tyr was significantly associated with doses of more than 70 mg/wk (odds ratio, 13.0; 95% confidence limit, 1.3 to 124.2), while doses of 20 to 70 mg/wk were associated with Asp36Tyr (partial r2 = .11; P = .004), CYP2C9*2 and *3 (r2 = .08; P = .01), and VKORC1*2 and *3 markers (r2 = .05; P = .05). All Asp36Tyr carriers also had VKORC1*1 tag–single nucleotide polymorphisms (tag-SNPs) indicating a new haplotype. Asp36Tyr was common in Jewish ethnic groups of Ethiopian (15%) and Ashkenazi (4%) origin. We suggest that Asp36Tyr is a new marker of the high end of the warfarin dosing range.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
M. H. Rosove and W. W. Grody
Should We Be Applying Warfarin Pharmacogenetics to Clinical Practice? No, Not Now
Ann Intern Med,
August 18, 2009;
151(4):
270 - 273.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. R. Langley, J. K. Booker, J. P. Evans, H. L. McLeod, and K. E. Weck
Validation of Clinical Testing for Warfarin Sensitivity: Comparison of CYP2C9-VKORC1 Genotyping Assays and Warfarin-Dosing Algorithms
J. Mol. Diagn.,
May 1, 2009;
11(3):
216 - 225.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Li, U. I. Schwarz, M. D. Ritchie, D. M. Roden, C. M. Stein, and D. Kurnik
Relative contribution of CYP2C9 and VKORC1 genotypes and early INR response to the prediction of warfarin sensitivity during initiation of therapy
Blood,
April 23, 2009;
113(17):
3925 - 3930.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
The International Warfarin Pharmacogenetics Consor
Estimation of the Warfarin Dose with Clinical and Pharmacogenetic Data
N. Engl. J. Med.,
February 19, 2009;
360(8):
753 - 764.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Aklillu, C. Leong, R. Loebstein, H. Halkin, and E. Gak
VKORC1 Asp36Tyr warfarin resistance marker is common in Ethiopian individuals
Blood,
April 1, 2008;
111(7):
3903 - 3904.
[Full Text]
[PDF]
|
|
|
|
|
