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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.
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Submitted August 1, 2006
Accepted November 3, 2006
A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance
Ronen Loebstein, Ilana Dvoskin, Hillel Halkin, Manuela Vecsler, Aharon Lubetsky, Gideon Rechavi, Ninette Amariglio, Yoram Cohen, Gie Ken-Dror, Shlomo Almog, and Eva Gak*
Institute of Clinical Pharmacology and Toxicology, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Institute of Human Genetics, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Cancer Research Center, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Department of Gynecologic Oncology, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Department of Epidemiology and Preventive Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
* Corresponding author; email: eva.gak{at}sheba.health.gov.il.
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 (doses 80-185 mg/week) and 8 sensitive patients (7-13 mg/week) and 99 unselected controls (8-105 mg/week). We identified a coding VKORC1 Asp36Tyr polymorphism in 7/15 resistant compared to 0/8 sensitive patients (p=0.026). Carriers of Asp36Tyr in the control group (8/99) required significantly higher warfarin doses 80.9±10.1 mg/week compared to 42.7±7.5 mg/week in non-carriers (F=9.79, p=0.002). Asp36Tyr was significantly associated with doses of >70mg/week (OR=13.0 [95%CL1.3-124.2]), while doses of 20-70mg/week were associated with Asp36Tyr (partial r2=0.11; p=0.004), CYP2C9*2/*3 (r2=0.08; p=0.01) and VKORC1*2/*3 markers (r2=0.05; p=0.05). All Asp36Tyr carriers also had VKORC1*1 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.
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