1.
ABCA1 Polymorphism Is Associated With the Warfarin-Induced Aortic Stiffness After Coronary Artery Bypass Surgery in the Chinese Population.
Liao, S, Zhou, Q, Zhang, Y
Journal of cardiovascular pharmacology. 2020;(3):360-366
Abstract
Warfarin is the most widely prescribed oral anticoagulant and is recommended for patients recovering from coronary artery bypass graft (CABG) with atrial fibrillation. Increasing evidence suggested that warfarin increased arterial stiffness in those patients. We aimed to examine the effect of warfarin therapy on aortic stiffness in patients who underwent CABG with or without postoperative warfarin treatment and explored the potential relationships of warfarin therapy with ABCA1 polymorphisms. This was a retrospect observational study of 24 patients who were continuously treated with warfarin were selected as the warfarin group and matched them by age (±3 years) and gender to 48 patients with nonuse of warfarin as the control group. The aortic stiffness, cholesterol efflux capacity, and plasma level of PIVKA-II were measured. Two ABCA1 polymorphisms were genotyped. Compared with baseline, treatment with warfarin for 1 year significantly increased the plasma level of PIVKA-II and aortic stiffness in pulse pressure and pulse wave velocity in patients after CABG. The increase of pulse wave velocity and plasma PIVKA-II level in the TT genotype was significantly greater than the CC genotype when comparing the -565C/T genotypes. The capacity of cholesterol efflux was significantly lower in the TT genotype at baseline and 1-year follow-up than the CC genotype. Postoperative treatment of warfarin for 1 year significantly increased aortic stiffness in patients who underwent CABG. ABCA1 -565C/T polymorphisms affected the cholesterol efflux capacity and were associated with the vitamin K status and the increased aortic stiffness after warfarin treatment in those patients.
2.
The influence of VKORC1 gene polymorphism on warfarin maintenance dosage in pediatric patients: A systematic review and meta-analysis.
Zhang, J, Tian, L, Zhang, Y, Shen, J
Thrombosis research. 2015;(5):955-61
Abstract
INTRODUCTION Warfarin is the most commonly used oral anticoagulant, however, there are large interindividual variations in dose responses. Genetic polymorphisms in CYP2C9, VKORC1 and CYP4F2 have been shown to play an important role in variations in the warfarin maintenance dose in adults, but their effects in children remain unclear. We aimed to investigate the effect of VKORC1 polymorphism on warfarin dosage in pediatric patients by meta-analysis. MATERIALS AND METHODS Using strict inclusion and exclusion criteria, we searched PubMed, EMBASE, Cochrane library, Chinese Biomedical Literature Database, CNKI and ChainInfo from 2004 to Mach 17th, 2015. The relationship between warfarin dose and two single nucleotide polymorphisms of the VKORC1 gene (at positions -1639 and 1173) were analyzed using Revman version 5.2.3 software. RESULTS AND CONCLUSIONS Eight studies were included in the meta-analysis, involving 610 pediatric patients. Patients that were VKORC1 -1639 GA, AA or A carriers required significantly lower warfarin dosage than GG carriers (the weighted mean difference in warfarin dose ranged from -26% to -50%). Additionally, the age of the patient and indication of warfarin (i.e. Fontan procedure) significantly affected warfarin dosage, but changes in the target international normalized ratio range had no effect. On the other hand, VKORC1 1173 polymorphisms showed no significant effect on warfarin dosage, which differs from adult patients. In conclusion, we found that VKORC1 -1639 gene polymorphisms have a moderate effect on warfarin dosage in pediatric patients, but clinical characteristics such as age and indication of warfarin also play an important role.
3.
Influence of CYP2C9 and VKORC1 genotypes on the risk of hemorrhagic complications in warfarin-treated patients: a systematic review and meta-analysis.
Yang, J, Chen, Y, Li, X, Wei, X, Chen, X, Zhang, L, Zhang, Y, Xu, Q, Wang, H, Li, Y, et al
International journal of cardiology. 2013;(4):4234-43
Abstract
BACKGROUND The main challenge for warfarin anticoagulation is the risk for hemorrhagic complications. Although certain pharmacogenetic factors may explain the individual variabilities about the therapeutic warfarin dose requirement, the genetic factors to warfarin hemorrhagic complications due to over-anticoagulation are largely unknown. To interpret the potential role of warfarin-related genotypes on over-anticoagulation and hemorrhagic complications, we conducted a meta-analysis based on 22 published studies. METHODS A comprehensive search was applied to the reports on over-anticoagulation and hemorrhagic complications published prior to December 31, 2012 in PubMed and EMBASE. References were identified by strict inclusion and exclusion criteria, with additional information obtained by consulting with the authors of primary studies. The roles of genotypes in CYP2C9 and VKORC1 on over-anticoagulation (INR > 4) and hemorrhagic complications were analyzed by Revman 5.0.2 software. RESULTS A total of 6272 patients in 22 reports were included in the meta-analysis, including studies of 18 from Caucasians (3 from both Caucasian and African-American), 3 from Asians, and 1 from Brazilians. Compared to CYP2C9 wild genotype (CYP2C9*1), both CYP2C9*2 (rs 1799853, c. 430 C > T, p. Arg144Cys) and *3 (rs 1057910, c. 1075 A >C, p. Ile359Leu) confer significantly higher risk for warfarin over-anticoagulation and hemorrhagic complications. After stratification by CYP2C9 allele status, significantly higher risk for hemorrhagic complications was found only in carriers of at least 1 copy of CYP2C9*3 [For total hemorrhages: *1/*3 HR: 2.05 (1.36-3.10), p < 0.001; *3/*3 HR: 4.87 (1.38-17.14), p = 0.01; For major hemorrhages: *1/*3 HR: 2.43 (1.17-5.06), p = 0.02; *3/*3 HR: 4.81 (0.95-24.22), p = 0.06]. Furthermore, similar susceptibility of total hemorrhage by CYP2C9 genotypes was observed in Caucasians and Asians. After stratification by the occurrence time, both CYP2C9*2 and *3 are risk factors for over-anticoagulation within 30 days of warfarin treatment [*2 HR: 1.64 (1.11-2.43), p = 0.01; *3 HR: 2.48 (1.56-3.96), p < 0.001], and only CYP2C9*3 showed higher risk for over-anticoagulation after 30 days [HR: 1.86 (1.08-3.20), P = 0.03]. For VKORC1 c. -1639G > A (rs 9923231) genotypes, GA and AA contributed significantly higher risk for over-anticoagulation within 30 days [HR: 2.14 (1.75-2.62), p < 0.001], but not for over-anticoagulation after 30 days [HR:0.78 (0.46-1.33), p = 0.36]. No significant association was found between VKORC1 genotypes and hemorrhagic complications. CONCLUSIONS Both CYP2C9 and VKORC1 genotypes are associated with an increased risk for warfarin over-anticoagulation, with VKORC1 c. -1639G > A more sensitive early in the course of anticoagulation. CYP2C9*3 is the main genetic risk factor for warfarin hemorrhagic complications.
4.
Estimation of the warfarin dose with a pharmacogenetic refinement algorithm in Chinese patients mainly under low-intensity warfarin anticoagulation.
Xu, Q, Xu, B, Zhang, Y, Yang, J, Gao, L, Zhang, Y, Wang, H, Lu, C, Zhao, Y, Yin, T
Thrombosis and haemostasis. 2012;(6):1132-40
Abstract
Pharmacogenetic (PG) dosing algorithms have been confirmed to predict warfarin therapeutic dose more accurately; however, most of them are based on standard intensity of warfarin anticoagulation, and their utility outside this range is limited. This study was designed to develop and validate a PG refinement algorithm in Chinese patients mainly under low-intensity warfarin anticoagulation. Consented Chinese-Han patients (n=310) under stable warfarin treatment were randomly divided into a derivation (n=207) and a validation cohort (n=103), with 83% and 80% of the patients under low-intensity anticoagulation, respectively. In the derivation cohort, a PG algorithm was constructed on the basis of genotypes (CYP2C9*3 and VKORC1-1639A/G) and clinical data. After integrating additional covariates of international normalised ratio (INR) values (INR on day 4 of therapy and target INR) and genotype of CYP4F2 (rs2108622), a PG refinement algorithm was established and explained 54% of warfarin dose variability. In the validation cohort, warfarin dose prediction was more accurate (p < 0.01) with the PG refinement algorithm than with the PG algorithm and the fixed dose approach (3 mg/day). In the entire cohort, the PG refinement algorithm could accurately identify larger proportions of patients with lower dose requirement (≤2 mg/day) and higher dose requirement (≥4 mg/day) than did the PG algorithm. In conclusion, PG refinement algorithm integrating early INR response and three genotypes (CYP2C9*3, VKORC1-1639A/G, CYP4F2 rs2108622) improves the accuracy of warfarin dose prediction in Chinese patients mainly under low-intensity anticoagulation.