Schwarz Ute I, Ritchie Marylyn D, Bradford Yuki, Li Chun, Dudek Scott M, Frye-Anderson Amy, Kim Richard B, Roden Dan M, Stein C Michael
Department of Medicine, Vanderbilt University School of Medicine, Nashville, USA.
N Engl J Med. 2008 Mar 6;358(10):999-1008. doi: 10.1056/NEJMoa0708078.
Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9), and of a key pharmacologic target of warfarin, vitamin K epoxide reductase (VKORC1), contribute to differences in patients' responses to various warfarin doses, but the role of these variants during initial anticoagulation is not clear.
In 297 patients starting warfarin therapy, we assessed CYP2C9 genotypes (CYP2C9 *1, *2, and *3), VKORC1 haplotypes (designated A and non-A), clinical characteristics, response to therapy (as determined by the international normalized ratio [INR]), and bleeding events. The study outcomes were the time to the first INR within the therapeutic range, the time to the first INR of more than 4, the time above the therapeutic INR range, the INR response over time, and the warfarin dose requirement.
As compared with patients with the non-A/non-A haplotype, patients with the A/A haplotype of VKORC1 had a decreased time to the first INR within the therapeutic range (P=0.02) and to the first INR of more than 4 (P=0.003). In contrast, the CYP2C9 genotype was not a significant predictor of the time to the first INR within the therapeutic range (P=0.57) but was a significant predictor of the time to the first INR of more than 4 (P=0.03). Both the CYP2C9 genotype and VKORC1 haplotype had a significant influence on the required warfarin dose after the first 2 weeks of therapy.
Initial variability in the INR response to warfarin was more strongly associated with genetic variability in the pharmacologic target of warfarin, VKORC1, than with CYP2C9.
代谢华法林的细胞色素P - 450 2C9（CYP2C9）酶以及华法林的关键药理学靶点维生素K环氧化物还原酶（VKORC1）的基因变异，导致患者对不同华法林剂量的反应存在差异，但这些变异在初始抗凝过程中的作用尚不清楚。
在297例开始接受华法林治疗的患者中，我们评估了CYP2C9基因型（CYP2C9 *1、2和3）、VKORC1单倍型（分为A和非A）、临床特征、治疗反应（通过国际标准化比值[INR]确定）和出血事件。研究结果包括达到治疗范围内首个INR的时间、首个INR大于4的时间、高于治疗性INR范围的时间、INR随时间的反应以及华法林剂量需求。
与非A/非A单倍型患者相比，VKORC1的A/A单倍型患者达到治疗范围内首个INR的时间缩短（P = 0.02），首个INR大于4的时间也缩短（P = 0.003）。相比之下，CYP2C9基因型不是达到治疗范围内首个INR时间的显著预测因素（P = 0.57），但却是首个INR大于4时间的显著预测因素（P = 0.03）。CYP2C9基因型和VKORC1单倍型在治疗的前2周后对所需华法林剂量均有显著影响。
华法林初始INR反应的变异性与华法林的药理学靶点VKORC1的基因变异性的关联比与CYP2C9的关联更强。
