Relative contribution of CYP2C9 and VKORC1 genotypes and early INR response to the prediction of warfarin sensitivity during initiation of therapy
Relative contribution of CYP2C9 and VKORC1 genotypes and early INR response to the prediction of warfarin sensitivity during initiation of therapy
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DOI：
10.1182/blood-2008-09-176859
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发表时间：
2009-04-23
期刊：
影响因子：
20.3
通讯作者：
Kurnik, Daniel
中科院分区：
文献类型：
--
作者：
Li, Chun;Schwarz, Ute I.;Kurnik, Daniel
CYP2C9 和 VKORC1 的基因变异强烈影响稳态华法林剂量。然而，这些变异也会影响华法林起始期间的早期国际标准化比值 (INR) 值。我们检查了 CYP2C9/VKORC1 基因型是否除了早期 INR 反应提供的信息之外还提供有关华法林敏感性的信息。在 214 名以 INR 指导剂量调整开始华法林的患者中，我们在调整早期（第 4-6 天）和第 1 周（第 7-9 天）INR 值后，确定 CYP2C9 和 VKORC1 基因型是否与华法林敏感性的早期测量相关（达到 INR 的时间 >= 治疗范围下限；达到 INR > 4 的时间；以及首次稳定的华法林剂量）。早期 INR 与所有结果相关（所有 P < .001），并且比基因型提供更多信息。对于达到 INR 大于或等于治疗范围下限的时间，将早期 INR 或基因型添加到基线模型（仅临床变量）将拟合优度 (R-2) 分别从 0.05 增加到 0.42 和 0.19（完整模型，R-2 = 0.46）。对于第一个稳定的华法林剂量，将早期 INR 或基因型添加到基线模型中，R-2 分别从 0.08 增加到 0.32 和 0.27（完整模型，R-2 = 0.40）。纳入第 1 周 INR 后，CYP2C9 (P = .08) 和 VKORC1 (P = .30) 与稳定的华法林剂量无关。因此，早期 INR 反应捕获了华法林启动期间 CYP2C9 和 VKORC1 基因型提供的大部分信息。 （血。2009；113：3925-3930）
Genetic variants in CYP2C9 and VKORC1 strongly affect steady-state warfarin dose. However, these variants also affect early international normalized ratio (INR) values during warfarin initiation. We examined whether CYP2C9/VKORC1 genotypes provide information about warfarin sensitivity additional to that provided by early INR responses. In 214 patients starting warfarin with INR-guided dose adjustments, we determined whether CYP2C9 and VKORC1 genotypes were associated with early measures of warfarin sensitivity (time to INR >= lower limit of therapeutic range; time to INR > 4; and first stable warfarin dose) after adjusting for early (days 4-6) and week 1 (days 7-9) INR values. Early INRs were associated with all outcomes (all P < .001) and were more informative than genotypes. For time to INR more than or equal to the lower limit of therapeutic range, adding either early INRs or genotypes to a baseline model (clinical variables only) increased the goodness-of-fit (R-2) from 0.05 to 0.42 and 0.19, respectively (full model, R-2 = 0.46). For first stable warfarin dose, adding either early INRs or genotypes to the baseline model increased the R-2 from 0.08 to 0.32 and 0.27, respectively (full model, R-2 = 0.40). After inclusion of week 1 INRs, CYP2C9 (P = .08) and VKORC1 (P = .30) were not associated with stable warfarin dose. Thus, much of the information provided by CYP2C9 and VKORC1 genotypes during warfarin initiation is captured by the early INR response. (Blood. 2009;113:3925-3930)