Instituto de Biología, Grupo de Genética de Poblaciones y Mutacarcinogénesis, Sede de Investigación Universitaria, Universidad de Antioquia, Medellin, Colombia.
Clin Appl Thromb Hemost. 2010 Feb;16(1):83-90. doi: 10.1177/1076029608330472. Epub 2009 Jun 29.
Warfarin is the most prescribed oral anticoagulant worldwide. Because of the complexity of warfarin therapy, we attempted to dissect genetic from bioenvironmental factors influencing warfarin dose responses in individuals of a genetic isolate of Hispanic ancestry. A total of 191 patients with standard values of international normalized ratio were recruited. Three groups with a significantly different warfarin dose response were identified, that is, sensitive (2.28 +/- 0.50 mg/d), intermediate (4.2 +/- 0.76 mg/d), and resistant (7.40 +/- 1.54 mg/d; Tukey test, P < .001). Age had a significant inverse correlation with warfarin dose (P < .001; effective dose diminished 0.56 mg/d/decade). Required doses were higher for individuals with CYP2C9 variants containing the allele 1 compared to those individuals with variants composed of other alleles (P = .006). Similarly, individuals with VKORC1-1639GG and VKORC1-1639GA genotypes also required higher doses compared to the AA genotype (P < .001). Evaluation of potential gene-gene interactions between CYP2C9 and VKORC1 polymorphisms showed significant differences in dosing for CYP2C9 genotypes within the VKORC1-1639G/A subgroup (P = .013). A stepwise multivariate linear regression analysis showed that 38.2% of the warfarin dose response variance was accounted for by a model involving age (20.9%), VKORC1-1639G/A (11.3%), and CYP2C91, *2, and *3 variants (7.1%). These results corroborate previous findings on warfarin pharmacogenetics and define a contrastable gene-bioenvironment interaction model suited to be used in Hispanic populations.
华法林是全球应用最广泛的口服抗凝药物。由于华法林治疗的复杂性，我们试图剖析影响具有西班牙裔血统遗传隔离个体对华法林剂量反应的遗传和生物环境因素。共招募了 191 例国际标准化比值（INR）正常的患者。确定了三组对药物反应差异显著的患者，即敏感组（2.28±0.50mg/d）、中间组（4.2±0.76mg/d）和抵抗组（7.40±1.54mg/d；Tukey 检验，P<.001）。年龄与华法林剂量呈显著负相关（P<.001；每十年减少有效剂量 0.56mg/d）。与携带其他等位基因的 CYP2C9 变体相比，携带等位基因1 的 CYP2C9 变体的个体需要更高的剂量（P=.006）。同样，与 AA 基因型相比，VKORC1-1639GG 和 VKORC1-1639GA 基因型的个体也需要更高的剂量（P<.001）。对 CYP2C9 和 VKORC1 多态性之间的潜在基因-基因相互作用的评估表明，在 VKORC1-1639G/A 亚组内 CYP2C9 基因型的给药存在显著差异（P=.013）。逐步多元线性回归分析显示，年龄（20.9%）、VKORC1-1639G/A（11.3%）和 CYP2C91、2 和3 变体（7.1%）解释了 38.2%的华法林剂量反应变异性。这些结果证实了先前关于华法林药物遗传学的研究结果，并确定了适合西班牙裔人群的可对比的基因-生物环境相互作用模型。
