VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation
VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation
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DOI：
10.1160/th05-04-0290
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发表时间：
2005-10-01
影响因子：
6.7
通讯作者：
Oldenburg, J
中科院分区：
文献类型：
--
作者：
Geisen, C;Watzka, M;Oldenburg, J
为了阐明VKORC 1序列变异在华法林敏感性中的作用，我们在来自德国西部的200名献血者中建立了VKORC 1基因位点的完整SNP图谱。欧洲人VKORC 1基因的几乎所有遗传变异性都由三种主要的单倍型反映。最近描述的与低华法林剂量需求相关的多态性（dbSNP：rs 9934438; dbSNP：rs 17878363）与VKORC 1 *2单倍型完全连锁不平衡。在两个香豆素敏感性增加（n = 14）或香豆素部分耐药（n=36）的欧洲患者队列中，两组之间以及与200名献血者对照组相比，VKORC 1 *2频率差异非常显著（香豆素敏感96%，香豆素抗性7%，对照42%），从而证明了这两种表型与VKORC 1单倍型之间的强关联（p = 1.6 × 10-（8），香豆素敏感; p = 1.9 × 10-（8），香豆素耐药）。对来自非裔美国人和中国人的VKORC 1基因型数据库的分析显示，这些人群中的单倍型频率与欧洲样本显著不同（对于VKORC 1 *2：欧洲人42%，中国人95%，非裔美国人14%）。这些观察结果表明VKORC 1是华法林反应种族差异的主要遗传调节因子。由于遗传性药效学（VKORC 1）和药代动力学（CYP 2C 9）因素占华法林反应个体间变异性的50%，因此这些遗传标记物可在未来研究中作为华法林剂量的临床相关预测因子。
In order to elucidate the role of VCORC1 sequence variants in warfarin sensitivity, we established a complete SNP map of the VKORC1 gene locus in 200 blood donors from Western Germany. Nearly all of the genetic variability of the VKORC1 gene in Europeans is reflected by three main haplotypes. Recently described polymorphisms associated with low warfarin dose requirement (dbSNP:rs9934438; dbSNP:rs17878363) were found in complete linkage disequilibrium with the VKORC1*2 haplotype. In two patient cohorts of European origin with either increased coumarin sensitivity (n = 14) or partial coumarin resistance (n=36) the VKORC1*2 frequency varied highly significant between the two groups and also when compared to 200 blood donor controls (coumarin sensitive 96%, coumarin resistant 7%, controls 42%) thus demonstrating a strong association between these two phenotypes and the VKORC1 haplotype (p = 1.6 x 10-(8) for coumarin sensitive and p = 1.9 x 10(-8) for coumarin resistant). Analysis of database derived VKORC1 genotypes of African Americans and Chinese revealed that haplotype frequencies in these populations differ significantly from the European sample (for VKORC1*2: Europeans 42%, Chinese 95%, African Americans 14%). These observations suggest VKORC1 as principal genetic modulator of the ethnic differences in warfarin response. Since hereditary pharmacodynamic (VKORC1) and pharmacokinetic (CYP2C9) factors account for up to 50% of the inter-individual variability of the warfarin response, these genetic markers may serve as clinically relevant predictors of warfarin dosing in future studies.