Warfarin Therapeutic Dose And VKORC1 Genetic Polymorphism Of Correlation Study

Objective:As a derivant of bishydroxyeoumarin, warfarin is the most commomly Preseribed oral antieogulant in the world from 40s 20th eentry when it was invented. For the narrow therapeutic index, it is easy to lead to adverse effects, such as thrombogenesis when the dose is in sufficient or bleeding when the dose is excessive. The risk of bleeding is increased several times, and even cause death when use warfarin as anticogulant, especially in the first weeks to months during the early stages of treatment. Another characteristic of warfarin therapy is the large different stable dose between different races as well as inter-individuals, with more than20-fold of the stable dose range. As such, it is difficult for clinicians to safely and efficiently prescribe warfarin for diffenent patients.Multiple factors affect the inter individual variation of warfarin dose, which can besorteded into genetic factors and non-genetic factors. Non-genetic factors inclued age, gender, body surface area, drug interactions dietary and morbid state. However, because the influence of non-genetic factors is limited, they are not the main reason of the variation of warfarin dose. Recently, with the rapid development of pharmacogenomics and elucidation of molecular mechanism of warfarin Pharmacologic action, the effect of genetic factors on the variation of warfarin dose is More and more important. At present, there are more than 30 genes related to the Pharmacodynamics and pharmacokinetics of warfarin, and CYP2C9 and VKORC1 are the two most important genetic factors.In the present study, we invest the association of VKORC1 (promoter region-16 39,the first intervening1173,3'noncoding region 3730) three gene polymorphism with warfarin in Yunnan of China, and may give the new evidence for molecular heredity and the dependent factors inter-subject of warfarin dose. Combined the genovariation, initiate INR and other clinical factorts to show the dose equation and can estimate warfarin dose. To invest the relevance of warfarin dose and VKORC1, and may give the new evidence for 昆明医学院硕士研究生论文mechanism and gene diagnosis for inter-individuals warfarin treatment.Methods:Three milliliter venous blood sample is obtained from each patient of valve replacement with warfarin using group. After adding EDTA to prevent the blood from coagulating, DNAwas extracted, Genotype and allele frequencies of polymorphism in three genes were examined by polymerase chain reaction and restriction fragement length polymorphism (PCR-RFLP) technique in 300 warfarin using patients. All statistics were performed on SPSS 15.0 and Arlequin.Results:Genotypes of VKORC1-1639 in warfarin using patients found three genotypes:homozygote-1639A/A, heterozygote-1639A/G, homozygote-1639G/G. type A/A were found in 204 cases (68%), type A/G were foud in 87 cases (29%), type G/G were foud in 9 cases (3%). allele frequency A 82.5%, allele frequency G 17.5%.Genotypes of VKORC1 1173 in warfarin using patients found three genotypes:homozygote 1173 C/C, heterozygote 1173 C/T, homozygote 1173 T/T. type C/C were foud in 0 cases (0%), type C/T were foud in 96 cases (32%), type T/T were found in 204 cases (68%), allele frequency C 16%, allele frequency T 84%. Genotypes of VKORC1 3730 in warfarin using patients found three genotypes:homozygote 3730 A/A, heterozygote 3730 A/G, homozygote 3730 G/G. type A/A were found in 14 cases (4.7%), type A/G were foud in 93 cases (31%), typeG/G were foud in 193 cases (64.3%). allele frequency A 20.2%, allele frequency G 79.8%.The genotype and allele frequencies of VKORC1 1173 polymorphism siffered significantly (p＜0.05). The genotype and allele frequencies of VKORC1-1639 and VKORC1 3730 polymorphism without significant difference (p＜0.05). There was significant correlation between warfarin dose and polymorphism for VKORC1-1639, VKORC1 1173, VKORC1 3730. logistic regression analysis three genotypes found that VKORC1-1639 AA type,VKORCl 1173 TT type and VKORC1 3730 GG type were sensitive.National statistical results of this study show that:with the Han in Xinjiang, Chinese singaporeans genotype and allele frequency difference was not statistically significant (p＜0.05), compared with foreign populations, whether genotype or other allele frequency distribution, with Malaysia, India, the Caucasus, the United Kingdom, France, Spain, the United States, more people, have a high degree of difference was statistically significant, indicating that gene in Han ethnic VKORC1-1639 to AA-type distribution in many other national there are significant differences in the distribution of characteristics. As can be seen from the table, the Western Caucasus, the United Kingdom. France, Spain, the United States population VKORC1-1639 AG-type genotype is the main, GG second type, AA type at least, the opposite in Chinese Han population.Conclusion:There were significant association between VKORC1-1639, VKORC1 1173 and VKORC1 3730 polymorphism and warfarin dose. VKORC1-1639 AA type,VKORC1 1173 TT type and VKORC1 3730 GG type were sensitive.