Influence Of Genetic Polymorphisms On Warfarin Stable Dose In Han Chinese Patients With Mechanical Heart Valve Replacement

Aims:Warfarin is the most widely used oral anticoagulant with a narrow therapeutic range, various inter-individual responses and high risks of bleeding or thromboembolism. Polymorphisms in CYP2C9and VKORC1are the major determinants of warfarin dosage requirement. Other genetic factors involved in vitamin K intake, as well as recycle and warfarin transportation may influence warfarin efficacy. MicroRNA, which regulates gene expression, might also play a role. The main aim of our present study was to investigate the influence of genetic polymoephisms and non-genetic factors on warfarin stable dosage (WSD) in Han Chinese patients with mechanical heart valve replacement.Methods:231Han-Chinese MHVR patients on WSD were enrolled. SNaPshot, direct sequencing and Pyrosequencing were used to analyze the genotypes of VKORC1-1639G>A, CYP2C9*3, CYP4F2rs2108622, EPHX1(rs4653436and rs1877724), GGCX(rs699664and rsl2714145), PROC rs5936, APOE (rs7412and rs429358), F2rs5896, miRNA133a-2-191G>A and miRNA133b-25ins/del A. The differences in average WSD among carriers with variant genotypes were analyzed by using nonparametric tests (Kruskal-Wallis H test for comparing three groups and Mann-Whitney U test for comparing two groups). Single and multiple linear regression analysis were used to investigate the impacts of the studied SNPs on WSD.Results:The frequencies of VKORC1-1639G>A were79.7%for AA,18.6%for GA,1.7%for GG The frequencies of CYP2C9*3were93.1%for*1/*1,6.9%for*1/*3. The frequencies of CYP4F2rs2108622were62.8%for GG,33.8%for GA,3.4%for AA. The frequencies of GGCX rs699664were44.2%for CC,46.8%for CT,9.1%for TT. The frequencies of GGCX rs12714145were40.1%for CC,45.2%for CT,14.7%for TT. The frequencies of EPHX1rs4653436were64.5%for GQ31.6%for GA,3.9%for AA.The frequencies of EPHX1rs1877724were43.3%for CC,48.1%, CT8.6%for TT. The frequencies of PROC rs5936 were24.7%for TT,54.1%for GT,21.2%for GG The frequencies of F2rs5896were29.0%for TT,52.4%for CT,18.6%for CC. The frequencies of APOE rs7412were82.7%for CC,17.3%for CT. The frequencies of APOE rs429358were TT77.5%,21.2%for CT,1.3%for CC. The frequencies of miR133a-2-191G>A were95.6%for GG,2.2%for GA,2.2%for AA, and the frequencies of miR133b-25ins/del A were92.2%for AA,7.8%for A/-, respectively. MiR133a-2-191G>A was excluded in the subsequent analysis due to deviating from Hardy-Weinberg equilibrium. Nonparametric tests showed significant differences in average WSD among patients with different genotypes of VKORC1-1639G>A, CYP2C9*3, CYP4F2rs2108622or GGCX (rs699664and rs12714145). Univariate regression analysis showed that age, BSA, VKORC1-1639G>A, CYP2C9*3, CYP4F2rs2108622, GGCX (rs699664and rs12714145) significantly influened warfarin stable dosage (P＜0.05). Stepwise linear regression showed that VKORC1-1639G>A, CYP2C9*3, CYP4F2rs2108622can explain25.1%,11.8%,2%,4%,2.1%of inter-individual variations in warfarin stable dosage respectively. EPHX1(rs4653436and rs1877724), GGCX(rs699664and rs12714145), PROC rs5936, APOE (rs7412and rs429358), F2rs5896, miRNA133a-2-191G>A or miRNA133b-25ins/del A did not influence warfarin stable dosage significantly.Conclusions:VKORC1-1639G>A, CYP2C9*3, CYP4F2rs2108622were major genetic determinants of warfarin stable dose in Han Chinese patients with MHVR. VKORC1-1639G>A, CYP2C9*3, CYP4F2rs2108622, age and BSA could respectively explain25.1%,11.8%,2%,4%and2.1%of inter-individual variations in warfarin stable dosage.