Effects of Pregnane X Receptor Genetic Polymorphisms on Stable Warfarin Doses
Effects of Pregnane X Receptor Genetic Polymorphisms on Stable Warfarin Doses
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DOI：
10.1177/1074248415578906
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发表时间：
2015-11-01
影响因子：
2.6
通讯作者：
Gwak, Hye Sun
中科院分区：
文献类型：
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作者：
Moon, Jung Yeon;Chang, Byung Chul;Gwak, Hye Sun
目的：孕烷 X 受体 (PXR) 是许多药物代谢酶的转录调节因子，包括细胞色素 P450 (CYP) 2C9。本研究的目的是评估 PXR 单核苷酸多态性 (SNP) 与稳定华法林剂量之间可能存在的关联。 方法：本研究纳入了华法林 EwhA-Severance 治疗 (EAST) 组的 201 名稳定华法林剂量患者。通过对维生素K环氧化物还原酶复合物1（VKORC1）rs9934438、CYP2C9 rs1057910、CYP4F2 rs2108622、组成型雄甾烷受体（CAR）rs2501873、肝细胞核等11个SNP进行基因分型，研究遗传多态性对稳定华法林剂量的影响。因子 4 (HNF4) rs3212198 和 PXR（rs3814055、rs1403526、rs3732357、rs3732360、rs2276707 和 rs2472682）。对CYP2C9野生型纯合子等位基因（AA）携带者进行亚组分析。结果：rs2472682（A>C）的1个PXR SNP在研究人群和亚组中与稳定华法林剂量显着相关；变异纯合子携带者所需的华法林日剂量比携带野生等位基因的携带者显着降低约0.8毫克。大约 43.7% 的华法林剂量需求总体个体差异可以通过多元回归模型来解释。 VKORC1、CYP2C9、年龄、CYP4F2、PXR rs2472682 和 CAR/HNF4 rs2501873/rs3212198 分别占变异性的 29.6%、5.9%、3.7%、2.3%、1.3% 和 0.9%。根据单变量和多变量分析，rs2472682 的 PXR SNP 仍然是 CYP2C9 野生型纯合子携带者的一个重要因素。 rs2501873/rs3212198/rs2472682 的 CAR/HNF4/PXR SNP 组合显示研究人群和亚组中分组基因型之间约 1 mg 剂量差异。结论：我们的结果表明 PXR 可能是稳定华法林剂量的决定因素。
Objective: Pregnane X receptor (PXR) is a transcriptional regulator of many drug-metabolizing enzymes including cytochrome P450 (CYP) 2C9. The objective of this study was to assess the possible association between PXR single-nucleotide polymorphisms (SNPs) and stable warfarin doses.Methods: A total of 201 patients with stable warfarin doses from the EwhA-Severance Treatment (EAST) Group of Warfarin were included in this study. The influence of genetic polymorphisms on stable warfarin doses was investigated by genotyping 11 SNPs, that is, vitamin K epoxide reductase complex 1 (VKORC1) rs9934438, CYP2C9 rs1057910, CYP4F2 rs2108622, constitutive androstane receptor (CAR) rs2501873, hepatocyte nuclear factor 4 (HNF4) rs3212198, and PXR (rs3814055, rs1403526, rs3732357, rs3732360, rs2276707 and rs2472682). Subgroup analysis was conducted on CYP2C9 wild-type homozygote allele (AA) carriers.Results: One PXR SNP of rs2472682 (A>C) exhibited significant association with stable warfarin doses in study population and the subgroup; variant homozygote carriers required significantly lower daily doses of warfarin than those carrying wild allele by about 0.8 mg. Approximate 43.7% of overall interindividual variability in warfarin dose requirement was explained by multivariate regression model. VKORC1, CYP2C9, age, CYP4F2, PXR rs2472682, and CAR/HNF4 rs2501873/rs3212198 accounted for 29.6%, 5.9%, 3.7%, 2.3%, 1.3%, and 0.9% of the variability, respectively. PXR SNP of rs2472682 remained a significant factor in CYP2C9 wild-type homozygote carriers based on univariate and multivariate analyses. The combination of CAR/HNF4/PXR SNPs of rs2501873/rs3212198/rs2472682 showed about 1 mg dose difference between grouped genotypes in study population and subgroup.Conclusion: Our results revealed that PXR could be a determinant of stable warfarin doses.