Novel VKORC1 mutations associated with warfarin sensitivity.
Warfarin is widely used anticoagulant drug for the prophylaxis and treatment of venous and arterial thromboembolic disorders and exerts its anticoagulant effect by inhibiting the vitamin K epoxide reductase. To determine the impact of genetic variants of the vitamin K epoxide reductase complex subunit 1 gene (VKORC1) on the anticoagulant response to warfarin, polymorphisms in exon 1, exon 3, and 3'-untranslated region (3' UTR) were assessed.


RESULTS
Sixty patients (34 males and 26 females) with stable INR (2-3) were selected from cardiology and anticoagulant clinic. Three VKORC1 frameshift mutations were detected. The first frameshift mutation was nucleotide deletion (91delCC) in exon 3 (1 patient). The second variation was nucleotide addition (51addCT) in exon 3 (2 patients). All the 3 patients reported bleeding during warfarin use, while no other bleeding was reported during the study period. Warfarin maintenance dose was significantly different between 3 patients with mutations and patients without mutations. The use of a fixed-dose warfarin for all patients and in range INR may not be sufficient for warfarin monitoring. Many factors including unknown ones may also play an important role in highly variable response among patients. Our data for the first time, suggested a new possible call for screening to reduce the risk of bleeding and guide for dosing.
Baniasadi
Shadi
S
Pharmaceutical Care Department, TB and Lung Disease Research Center, Shahid Beheshti University, M.C., Tehran, Iran.
Beizaee
Samira
S
Kazemi
Bahram
B
Behzadnia
Neda
N
Shafaghi
Bijan
B
Bandehpour
Mojgan
M
Fahimi
Fanak
F
D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000494:pharmacology*; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000494:pharmacology*
D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases