Ability of VKORC1 and CYP2C9 to predict therapeutic warfarin dose during the initial weeks of therapy.
Ability of VKORC1 and CYP2C9 to predict therapeutic warfarin dose during the initial weeks of therapy.
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DOI：
10.1111/j.1538-7836.2009.03677.x
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发表时间：
2010-01
期刊：
影响因子：
--
通讯作者：
Gage BF
中科院分区：
文献类型：
--
作者：
Ferder NS;Eby CS;Deych E;Harris JK;Ridker PM;Milligan PE;Goldhaber SZ;King CR;Giri T;McLeod HL;Glynn RJ;Gage BF
CYP 2C 9和VKORC 1基因型可预测华法林治疗开始时的治疗剂量;然而，遗传信息在一周或更长时间后的预测能力尚不清楚。专家们假设，一旦国际标准化比值（INR）值可用，基因型就变得无关紧要，因为INR反应反映了华法林的敏感性。我们对预防复发性静脉血栓栓塞（PREVENT）试验的参与者进行了基因分型，这些参与者患有特发性静脉血栓栓塞，并使用标准给药方案开始低强度华法林（治疗INR 1.5-2.0）。为了建立药物遗传学模型，我们量化了基因型、临床因素、既往剂量和INR对223名PREVENT参与者华法林治疗剂量的影响，这些参与者被随机分配接受华法林治疗并达到稳定的治疗INR。使用第0天（治疗开始前）数据的药物遗传学模型解释了54%的治疗剂量变异性（R2）。由于既往剂量和INR反应的贡献增加，R2在第7天增加至68%，在第14天增加至75%，在第21天增加至77%。虽然CYP 2C 9和VKORC 1基因型是每个每周间隔治疗剂量的显著独立预测因子，但其预测能力的大小随时间推移而降低：基因型的部分R2在第0天为43%，第7天为12%，第14天为4%，第21天为1%。在华法林治疗的前几周，INR和既往剂量越来越能预测治疗剂量，基因型变得不那么相关。然而，在第7天，基因型仍然具有临床相关性，占治疗剂量变异性的12%。
CYP2C9 and VKORC1 genotypes predict therapeutic warfarin dose at initiation of therapy; however, the predictive ability of genetic information after a week or longer is unknown. Experts have hypothesized that genotype becomes irrelevant once International Normalized Ratio (INR) values are available because INR response reflects warfarin sensitivity. We genotyped the participants in the Prevention of Recurrent Venous Thromboembolism (PREVENT) trial, who had idiopathic venous thromboemboli and began low-intensity warfarin (therapeutic INR 1.5-2.0) using a standard dosing protocol. To develop pharmacogenetic models, we quantified the effect of genotypes, clinical factors, previous doses, and INR on therapeutic warfarin dose in the 223 PREVENT participants who were randomized to warfarin and achieved stable therapeutic INRs. A pharmacogenetic model using data from day 0 (before therapy initiation) explained 54% of the variability in therapeutic dose (R2). The R2 increased to 68% at day 7, 75% at day 14, and 77% at day 21, because of increasing contributions from prior doses and INR response. Although CYP2C9 and VKORC1 genotypes were significant independent predictors of therapeutic dose at each weekly interval, the magnitude of their predictive ability diminished over time: partial R2 of genotype was 43% at day 0, 12% at day 7, 4% at day 14, and 1% at day 21. Over the first weeks of warfarin therapy, INR and prior dose become increasingly predictive of therapeutic dose, and genotype becomes less relevant. However, at day 7, genotype remains clinically relevant, accounting for 12% of therapeutic dose variability.
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影响因子：
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通讯作者：
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