University of Murcia, Centro de Hemodonación, Murcia, Spain.
J Thromb Haemost. 2010 May;8(5):1012-7. doi: 10.1111/j.1538-7836.2010.03800.x. Epub 2010 Feb 9.
There is currently intense debate as to whether pharmacogenetic algorithms for estimating the initial dose of coumarins provide a more accurate dose than the fixed-dose approach. Recently, it has been suggested that the greatest benefit of pharmacogenetic algorithms is observed in patients with extreme dose requirements.
To identify clinical and genetic factors that better characterize patients who need extreme acenocoumarol doses for steady anticoagulation state.
PATIENTS/METHODS: We reviewed 9538 patients with a steady acenocoumarol dose from three Spanish hospitals, selecting 83 who took <or= 5.00 mg week(-1) (percentile 5, p5) and 203 taking >or= 30.00 mg week(-1) (p95). We also selected patients matched by gender and age taking 13.50-14.00 mg week(-1) (p50). We genotyped VKORC1 (rs9923231), CALU (rs1043550), GGCX (rs699664), CYP2C9 (rs1799853; rs1057910), CYP4F2 (rs2108622) and F7 (rs5742910) single-nucleotide polymorphisms (SNPs).
Comparison between p5 and p95 revealed five parameters with significant differences: body surface area (BSA) (P = 0.006), age, VKORC1, CYP2C9 and CYP4F2 genotypes (all P < 0.001). First VKORC1, and second, CYP2C9 SNPs played a strong effect by determining extreme doses, particularly in p95. Only one out of 203 p95 had the VKORC1 A-1639A genotype, but this subject was CYP2C9*1/1. In contrast, nine out of 83 p5 carried the VKORC1 G-1639G genotype, although six of them were CYP2C93 homozygotes and another two were heterozygotes. Surprisingly, CYP4F2 V433M SNP displayed prevalences that suggest that its influence might only be evident when patients are treated with high doses.
Two clinical data, age and BSA, and three SNPs in the VKORC1, CYP2C9 and CYP4F2 genes strongly predict outlier patients treated with acenocoumarol.
目前，关于估算香豆素初始剂量的药物遗传学算法是否比固定剂量方法更能提供准确的剂量存在激烈的争论。最近，有人提出，药物遗传学算法的最大益处是在需要极端剂量的患者中观察到。
确定更好地描述需要稳定抗凝状态下极端乙酰香豆素剂量的患者的临床和遗传因素。
患者/方法：我们回顾了来自西班牙三家医院的 9538 名稳定乙酰香豆素剂量的患者，选择了 83 名服用<5.00 毫克/周（第 5 百分位，p5）和 203 名服用>30.00 毫克/周（p95）的患者。我们还选择了性别和年龄匹配的患者，服用 13.50-14.00 毫克/周（p50）。我们对 VKORC1(rs9923231)、CALU(rs1043550)、GGCX(rs699664)、CYP2C9(rs1799853; rs1057910)、CYP4F2(rs2108622)和 F7(rs5742910)单核苷酸多态性（SNP）进行了基因分型。
p5 与 p95 之间的比较显示，有五个参数存在显著差异：体表面积（BSA）（P=0.006）、年龄、VKORC1、CYP2C9 和 CYP4F2 基因型（均 P<0.001）。首先是 VKORC1，其次是 CYP2C9 SNP 通过确定极端剂量发挥了强大作用，尤其是在 p95 中。在 203 名 p95 患者中，只有 1 名患者携带 VKORC1 A-1639A 基因型，但该患者为 CYP2C9*1/1。相比之下，83 名 p5 患者中有 9 名携带 VKORC1 G-1639G 基因型，尽管其中 6 名是 CYP2C93 纯合子，另外 2 名是杂合子。令人惊讶的是，CYP4F2 V433M SNP 的流行率表明，只有当患者接受高剂量治疗时，其影响才可能明显。
年龄和 BSA 这两个临床数据，以及 VKORC1、CYP2C9 和 CYP4F2 基因中的三个 SNP 强烈预测了用乙酰香豆素治疗的离群患者。
