TY - JOUR
T1 - A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance
AU - Loebstein, Ronen
AU - Dvoskin, Ilana
AU - Halkin, Hillel
AU - Vecsler, Manuela
AU - Lubetsky, Aharon
AU - Rechavi, Gideon
AU - Amariglio, Ninette
AU - Cohen, Yoram
AU - Ken-Dror, Gie
AU - Almog, Shlomo
AU - Gak, Eva
PY - 2007/3/15
Y1 - 2007/3/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33947231296&partnerID=8YFLogxK
U2 - 10.1182/blood-2006-08-038984
DO - 10.1182/blood-2006-08-038984
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C2 - 17110455
AN - SCOPUS:33947231296
SN - 0006-4971
VL - 109
SP - 2477
EP - 2480
JO - Blood
JF - Blood
IS - 6
ER -