Study On Venous Thromboembolism And The Related Genes Of Warfarin

BackgroundVenous thromboembolism is a major global burden of disease,pulmonary embolism is the third most common acute cardiovascular disease after acute myocardial infarction and stroke,causing venous thrombosis risk factors include age,obesity,recent surgical history,cancer,medical disease,etc.Warfarin is common used to treat anticoagulant drugs in venous thromboembolism,but warfarin between different individuals need a very different dose,or even a difference of more than 20 times,inadequate warfarin dose not achieve effect,excessive can cause bleeding risk,so adjust warfarin dose puzzled clinicians,The effects of warfarin dose include non-genetic factors(height,age,body weight,etc.)and genetic factors(VKORC1,CYP2C9,GGCX,PROC,KEPHX1,CYP4F2 and other genetic polymorphisms),VKORC1,CYP2C9 gene polymorphism is mainly decided to the required dose of warfarin between different people,and more and more studies are now focused on warfarin maintenance dose prediction models,which currently have the authority and use of more predictive models,namely International Warfarin Pharmacogenetics— Cortortium(IWPC),This study aims to analyze the risk factors for venous thromboembolism,the distribution of VKORC1 and CYP2C9 gene,the influence of VKORC1 and CYP2C9 gene polymorphisms on warfarin dose and establish a warfarin maintenance dose prediction model in patients with venous thromboembolism.Objective1.Analysis of the risk factors of venous thromboembolism is to prevent and reduce the occurrence of venous thromboembolism.2.Detecting CYP2C9 and VKORC1 genotypes in patients with venous thromboembolism by using gene chip,studing the effect of genotype polymorphism on warfarin maintenance dose,and establishing a warfarin maintenance Dose prediction model in patients with venous thromboembolism.MethodsThis is a retrospective study,the study selected 90 cases of patients which received venous ultrasound and / or chest CTA or venography and diagnosed with venous thromboembolism from June 2015 to February 2017 in GuangZhou first people's Hospital,analysis of the risk factors and the anticoagulation method of venous thromboembolism,--of these,65 were detected CYP2C9 and VKORC1 genotypes by using gene chip,--all of which were orally administered to the same manufacturer of warfarin(3 mg / tablet,Orion Corporation,Finland)and warfarin has now reached a steady dose(continuous monitoring 3 times and INR 2-3).Collecting the general clinical data(sex,age,height,weight,type of venous thromboembolism,etc.)from 65 patients.Extraction of peripheral venous blood used to detect CYP2C9 and VKORC1 gene polymorphism type,CYP2C9 * 1 / * 1 was found in 60 patients(92.3%),CYP2C9 * 1 / * 3 patients(7.7%),51 patients with VKORC1 gene A/A type(78.5%),13 cases(20%)of A/G type and 1 case(1% of G/G type),Grouped according to VKORC1 gene and CYP2C9 gene polymorphism and analyzed by independent sample t test.The effects of VKORC1 and CYP2C9 gene polymorphisms on warfarin dose were analyzed by simple linear regression analysis.The effects of sex,age,height,body weight,venous thrombosis type,VKORC1 and CYP2C9 gene polymorphism on warfarin dose were analyzed by simple linear regression analysis.Multiple linear regression was used to establish a method Patient dose of warfarin in patients with venous thromboembolism.Results1.Among the 90 patients with VTE,60(66.7%)were DVT,of these 58 cases were deep venous thrombosis of lower extremities,2 cases were upper limb deep vein thrombosis;10 cases were PE(11.1%);20 cases were DVT + PE(22.2%).2.Of the 90 patients with VTE,70(77.8%)were treated with warfarin anticoagulant,19(21.1%)with a new anticoagulant rivaroxaban,and 1 patient(1.1%)using low molecular weight heparin anticoagulant.3.In this study,VTE patients with more frequent risk factors for age,obesity,lower extremity edema,bed rest.4.CYP2C9 *1/*1+ VKORC1 A/A?CYP2C9 *1/*1+VKORC1 A/G?CYP2C9 *1/*1+VKORC1 G/G?CYP2C9 *1/*3+VKORC1 A/A?CYP2C9 *1/*3+VKORC1 A/G were detected for the study of 65 VTE patients.accounting for 72.3%,18.5%,1.5%,6.2% and 1.5% respectively.CYP2C9 genotype detected CYP2C9 *1/ *1,CYP2C9 *1/ *3,accounting for 92.3%,7.7%,not detected CYP2C9 *1/*2?CYP2C9 *2/*2?CYP2C9 *2/*3?CYP2C9 *3/*3.VKORC1 genotype detected VKORC1 A / A,VKORC1 A/G,VKORC1 G/G type,accounting for 78.5%,20%,1.5% respectively.The CYP2C9 allele was CYP2C9 * 1 and CYP2C9 * 3,accounting for 96.2% and 3.8% respectively.The VKORC1 alleles were VKORC1 A and VKORC1 G,accounting for 88.5% and 11.5% respectively.5.only Considering the influence of VKORC1 gene polymorphism,VTE patients with VKORC1 genotype A/A group was significantly lower of warfarin maintenance required daily than that in A/G + G/G group,and the difference was statistically significant.[(2.79 ± 0.89)mg vs(4.34 ± 1.05)mg,P<0.001]6.only Considering the influence of CYP2C9 gene polymorphism,VTE patients with the CYP2C9 genotype *1/ *1 was significantly higher of warfarin maintenance required daily than that in *1/*3 group,and the difference was statistically significant.[(3.21 ± 1.09)mg vs(2.1 ± 0.98)mg,P=0.03].7.The age,height,body weight,VKORC1,CYP2C9 gene polymorphism had significant difference in the maintenance dose of warfarin by simple linear regression analysis(P<0.05);age,height,body weight,the polymorphisms of VKORC1 and CYP2C9 genes can respectively explain 7.3%,10.1%,10.8%,16.8%,12.0% VTE patients warfarin different doses of different individuals.venous thromboembolism type,sex had no significant difference in the dose of warfarin(P>0.05).8.To maintain the required daily dose of warfarin as the dependent dose,sex(female = 0,male = 1),age,height(cm),body weight(kg),venous thromboembolism type(1),CYP2C9 genotype(* 1 / * 1 = 0,* 1 / * 3 = 1),VKORC1 genotype(A/A = 0,A/G + G/G = 1)as an independent variable.By multivariate stepwise linear regression analysis,dose model of warfarin in patients with venous thromboembolism was established as dose(mg)= 5.058 + 1.322 * VKORC1-1.535 * CYP2C9-0.031 * age.This study established a predictive model of warfarin maintenance dose in patients with venous thromboembolism,and that 44.2% of warfarin maintains the individual dose required for the dose.Conclusion1.In this study,patients with venous thrombosis prefer to occur in both lower extremities and choose warfarin anticoagulation mainly.2.In this study,VKORC1 and CYP2C9 genotypes were mainly A/A,* 1 / * 1 type,respectively.3.Age,height,body weight,VKORC1,CYP2C9 gene polymorphism had significant effects on the maintenance dose of warfarin,and The polymorphisms of VKORC1 and CYP2C9 genes were the main determinants.4.The establishment of a dose model of warfarin in patients with venous thromboembolism was included in the VKORC1,CYP2C9,age of three independent variables,which could explain 44.2% of the individual differences in the required dose of warfarin.