Influence Of PXR And VKORC1 Gene Polymorphisms On Warfarin Maintain Dose

Objective:Warfarin dose requirement was influenced by many gene polymorphisms. Nuclear receptor PXR is a transcriptional control factor and control the expression of genes related to metabolism and transport process of warfarin. Recent genome-wide association studies confirmed VKORC1 as the principal genetic determinants of warfarin dose. The aims of our study were to investigate the polymorphisms of pregnane X receptor (PXR) and Vitamin K epoxide reductase complex subunit 1 (VKORC1-1639G>A) in patients with heart valve replaced as well as the possible relationship between the individual warfarin maintain dosage requirements and these genetic polymorphisms in Chinese.Methods:Basic clinical feature and blood samples were collected from 215 Chinese patients who received mechanicalness cardiac valve replacement operated in Xiangya Hospital with stable warfarin dose requirement and an international normalized ratio (INR) of the prothrombin time within the target range of 1.5-3.0. The polymorphism of VKORC1-1639G>A in 215 patients was detected by using PCR-RFLP. PXR 6bp deletions (rs3842689) genotypes were determined by using Allelic Special-Touch down PCR method. The genotype and allelic frequencies were calculated and the individual warfarin maintenance dosage requirements were analyzed. The contributions of gender, age and body weight to warfarin dose requirement were also investigated.Results:AA genotype was found in 186 patients (86.5%), AG genotype in 28 patients (13.0%) and GG genotype in 1 patient (0.5%). The mean warfarin dosage was significantly higher in patients with AG/GG genotype than that in patients with AA genotype, AA (2.8±1.0mg), AG/GG (3.8±1.0mg), (P＜0.001). The frequencies of the PXR 6bp deletion WW, WM, MM genotypes were 54.4%(117/215),37.2%(80 /215) and 8.4%(18/215), respectively. The mean warfarin dosages were:WW (2.9±1.1mg), WM (3.0±1.0mg), and MM (3.1±0.8mg). It showed no significant difference in mean warfarin dosage among the genotypes of PXR 6bp deletions (P=0.764). After adjusted VKORC1-1639G>A and gender, there were also no significant difference in warfarin dosage among the genotypes of PXR 6bp deletions. The warfarin dose of men was significantly higher than women, their dose were 3.2±1.1 mg/day,2.8±1.0 mg/day respectively,P=0.018. Body weight and the number of replaced valves except for age were found to be potentially associated with warfarin dose requirements. In the multiple linear regression model, the combination of gender and VKORC1-1639G>A could explain 12.2% of the variance in warfarin dose requirements.Conclusions:Polymorphism of VKORC1-1639G>A is dominant factor causing difference of individual warfarin maintain dosage requirements in Han Chinese, while PXR 6bp deletion (rs3842689) had no significant influence on patients'warfarin dosage requirements. The warfarin dose of men was significantly higher than women. The number of replaced valves and body weight can positively influence patients'warfarin dose requirement. Age had no significant influence on patients'warfarin dose requirement.