Department of Laboratory Medicine, Paracelsus Medical University and Universitätsklinikum Salzburg, Austria.
Eur J Clin Pharmacol. 2010 Mar;66(3):253-60. doi: 10.1007/s00228-009-0768-7. Epub 2009 Dec 18.
The variability in warfarin dose requirement is attributable to genetic and environmental factors. Acenocoumarol (AC) and phenprocoumon (PC) are coumarin derivates widely prescribed in European countries for the prevention and treatment of thromboembolic events. The aim of our study was to investigate the contribution of genes involved in the vitamin K cycle to AC and PC maintenance doses.
Common single nucleotide polymorphisms (SNPs) in the genes encoding cytochrome P450 family member 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), gamma-glutamyl carboxylase (GGCX), calumenin (CALU) and apolipoprotein E (APOE) were studied in 206 patients receiving AC or PC.
Compared to patients with the VKORC1 C1173C genotype, maintenance doses for AC or PC were reduced to 74.6 or 70.2% in heterozygous C1173T subjects and to 48.6 or 48.1% in homozygous T1173T subjects (P < 0.0001). Furthermore maintenance doses for AC and PC were significantly lower in heterozygous CYP2C913, CYP2C923, and in CYP2C933 homozygote individuals compared to homozygous CYP2C911 subjects (P = 0.0004 and P = 0.0017, respectively). A multiple regression model including age, sex, last INR, VKORC1, and CYP2C9 genotypes explained ~50% of the variability in AC/PC dose requirements. CALU genotype combinations showed minor effects on PC dose requirements. No associations with AC or PC dose requirements were observed for sequence substitutions in the GGCX or APOE genes.
These results reveal that interindividual variability in weekly AC and PC maintenance dose requirement is mainly dependent on the VKORC1 1173C>T and the CYP2C9*3 alleles. VKORC1 and CYP2C9 genotyping might provide helpful information to prevent serious bleeding events in subjects receiving AC or PC.
华法林剂量需求的变异性归因于遗传和环境因素。醋硝香豆素（AC）和苯丙香豆素（PC）是在欧洲国家广泛用于预防和治疗血栓栓塞事件的香豆素衍生物。我们研究的目的是研究参与维生素 K 循环的基因对 AC 和 PC 维持剂量的贡献。
研究了接受 AC 或 PC 治疗的 206 例患者中编码细胞色素 P450 家族成员 2C9（CYP2C9）、维生素 K 环氧化物还原酶复合物亚基 1（VKORC1）、γ-谷氨酰羧化酶（GGCX）、钙网蛋白（CALU）和载脂蛋白 E（APOE）的基因中的常见单核苷酸多态性（SNP）。
与 VKORC1 C1173C 基因型患者相比，AC 或 PC 维持剂量在杂合子 C1173T 受试者中降低至 74.6%或 70.2%，在纯合子 T1173T 受试者中降低至 48.6%或 48.1%（P<0.0001）。此外，与 CYP2C911 纯合子受试者相比，AC 和 PC 的维持剂量在杂合子 CYP2C913、CYP2C923 和 CYP2C933 个体中显著降低（P=0.0004 和 P=0.0017）。包括年龄、性别、最后 INR、VKORC1 和 CYP2C9 基因型在内的多元回归模型解释了 AC/PC 剂量需求变化的约 50%。CALU 基因型组合对 PC 剂量需求的影响较小。在 GGCX 或 APOE 基因的序列取代与 AC 或 PC 剂量需求无关。
这些结果表明，个体间对华法林每周 AC 和 PC 维持剂量需求的变异性主要取决于 VKORC1 1173C>T 和 CYP2C9*3 等位基因。VKORC1 和 CYP2C9 基因分型可能为预防接受 AC 或 PC 治疗的患者发生严重出血事件提供有帮助的信息。
