Polymorphisms in the VKORC1 gene are associated with an interindividual variability in the dose-anticoagulant effect of warfarin in very elderly patients

Abstract

Objective To investigate the association between warfarin drug effects and vitamin K epoxide reductase complex subunit 1 (VKORC1)-1639 G/A gene polymorphisms in Han Chinese very elderly patients. Methods The subjects were elderly patients aged more than 60 years, with stable anticoagulation with warfarin and the target international normalized ratio(INR), who were hospitalized in Beijing Friendship Hospital, Capital Medical University from August 2009 to August 2016. The patients were divided into the very elderly group and aged group. The first record of warfarin dosage, the duration of achieving stable dosage (defined as the initial stage of treatment) and warfarin stable dosage were recorded. The bleeding and embolism events during early treatment were observed. After INR was at the steady state, genotyping for the VKORC1-1639 G/A alleles were tested. The effects of drugs and complications in warfarin initiation therapy were also investigated. Results A total of 322 patients were enrolled, including 300 cases of atrial fibrillation and 22 cases of pulmonary embolism. The very elderly group had 200 cases, including 110 males and 90 females; their ages ranged from 75 to 96 years, the average age was (83+ 7). The aged group had 122 cases, including 68 males, 54 females, their ages ranged from 60 to less than 75 years, the average age was (67±8). The VKORC1-1639 G/A genotype included 256 cases of AA type (79.5%) which contained 150 males and 106 females, and 62 cases of type AG (19.3%) which contained 26 males and 36 females. The GG type included 4 cases (1.2%), containing 2 males and 2 females. Genotype distribution accorded with the law of genetic equilibrium. There was no significant difference in VKORC1-1639 G/A genotype distribution between the aged group and the very elderly group (P>0.05). The carriers of VKORC1-1639 AG+ GG genotype had a significantly higher warfarin stable dosage than those of AA genotype [(2.90±1.39)mg vs. (2.00±1.14)mg, t=5.39, P<0.01]. In the same genotype, the very elderly patients had a decreased warfarin stable dosage compared with the aged patients [AA: (1.62±1.24)mg vs. (2.58±0.98)mg, t=6.68, P<0.01; AG+ GG: (2.43±0.55)mg vs. (3.36±1.52)mg, t=3.97, P<0.01]. The AG+ GG patients have a longer time to achieve stable dosage-effect relation compared with AA genotype [(18.9±2.8)d vs. (11.2±2.5)d, t=4.28, P=0.01]. Conclusions Warfarin stable dosage was related to patient age and VKORC1-1639 gene polymorphism. According to the results of VKORC1-1639 genotype testing to adjust warfarin dose maybe have some clinical significance in Han elderly patients. Key words: Warfarin; Genotype; Aged