Genotypes of vitamin K epoxide reductase, γ-glutamyl carboxylase, and cytochrome P4502C9 as determinants of daily warfarin dose in Japanese patients
Genotypes of vitamin K epoxide reductase, γ-glutamyl carboxylase, and cytochrome P4502C9 as determinants of daily warfarin dose in Japanese patients
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DOI：
10.1016/j.thromres.2006.09.007
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发表时间：
2007-01-01
影响因子：
7.5
通讯作者：
Miyata, Toshiyuki
中科院分区：
文献类型：
--
作者：
Kimura, Rina;Miyashita, Kotaro;Miyata, Toshiyuki
华法林抗凝作用所需的剂量存在较大的个体间差异。本研究旨在确定四种基因，维生素K环氧化物还原酶（VKORC 1），γ-谷氨酰羧化酶（GGCX），钙调素（CALU）和细胞色素P450 2C 9（CYP 2C 9）对日本患者缺血性卒中后华法林维持剂量的贡献。我们招募了93名接受稳定抗凝治疗的患者，目标国际标准化比值（INR）为1.6-2.6。我们对参与维生素K循环的三个基因中的11个代表性单核苷酸多态性（SNP）和CYP 2C 9中的42613 A> C SNP（称为CYP 2C 9 *3）进行了基因分型，然后检查了这些基因型与华法林维持剂量的相关性（平均值+/- SD=2.96 +/- 1.06 mg/天）。我们发现华法林有效剂量与VKORC 1中的-1639G > A（p=0.004）和3730 G> A（p=0.006）基因型、GGCX中的8016 G> A基因型（p=0.022）和CYP 2C 9中的42613 A> C基因型（p=0.015）相关。多元回归模型包括年龄、性别、体重和3个基因多态性，占华法林剂量总变异的33.3%。VKORC 1 - 1639 G> A对华法林剂量个体间差异的贡献率为5.9%，CYP 2C 9 42613 A> C为5.2%，GGCX 8016 G> A为4.6%。除了VKORC 1和CYP 2C 9的多态性，我们发现GGCX 8016 G> A导致错义突变R325 Q，作为日本患者华法林维持剂量的遗传决定因素。(C)2006爱思唯尔有限公司保留所有权利。
The dose required for the anticoagulant effect of warfarin exhibits large inter-individual variations. This study sought to determine the contribution of four genes, vitamin K epoxide reductase (VKORC1), gamma-glutamyl carboxytase (GGCX), calumenin (CALU), and cytochrome P450 2C9 (CYP2C9) to the warfarin maintenance dose required in Japanese patients following ischemic stroke. We recruited 93 patients on stable anticoagulation with a target International Normalized Ratio (INR) of 1.6-2.6. We genotyped eleven representative single nucleotide polymorphisms (SNPs) in the three genes involved in vitamin K cycle and the 42613A > C SNP in CYP2C9, known as CYP2C9*3, and then examined an association of these genotypes with warfarin maintenance doses (mean +/- SD=2.96 +/- 1.06 mg/day). We found an association of effective warfarin dose with the -1639G > A (p=0.004) and 3730G > A genotypes (p=0.006) in VKORC1, the 8016G > A genotype in GGCX (p=0.022), and the 42613A > C genotype in CYP2C9 (p=0.015). The model using the multiple regression analysis including age, sex, weight, and three genetic polymorphisms accounted for 33.3% of total variations in warfarin dose. The contribution to inter-individual variation in warfarin dose was 5.9% for VKORC1 -1639G > A, 5.2% for CYP2C9 42613A > C, and 4.6% for GGCX 8016G > A. In addition to polymorphisms in VKORC1 and CYP2C9, we identified GGCX 8016G > A, resulting in the missense mutation R325Q, as a genetic determinant of warfarin maintenance dose in Japanese patients. (C) 2006 Elsevier Ltd. All rights reserved.