Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups
Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups
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DOI：
10.1182/blood-2009-12-255992
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发表时间：
2010-05-06
期刊：
影响因子：
20.3
通讯作者：
Wagner, Michael J.
中科院分区：
文献类型：
--
作者：
Limdi, Nita A.;Wadelius, Mia;Wagner, Michael J.
与仅基于临床和人口统计学因素的算法相比，结合CYP 2C 9和VKORC 1 - 1639 G> A的华法林给药算法改善了剂量预测。然而，这些算法比亚洲人或黑人更好地捕获白人的剂量变异性。在此，我们评估了在亚洲人（n = 1103）、黑人（n = 670）和白人（n = 3113）中，除了VKORC 1 - 1639 G>A所解释的之外，其他VKORC 1多态性和单倍型是否解释了华法林剂量的额外变化。参与者是从11个国家招募的，这是国际遗传药理学联盟努力的一部分。采用单变量和多变量线性回归评估个体VKORC 1单核苷酸多态性（SNP）和单倍型对华法林剂量的影响。VKORC 1 - 1639 G>A和1173 C>T分别解释了所有3个种族组中剂量的最大差异。纳入额外的VKORC 1 SNP或单倍型并没有进一步改善剂量预测。VKORC 1解释了白人中剂量的变异性大于黑人和亚洲人。VKORC 1解释的剂量变异百分比在人种间的差异主要由-1639 A（或1173 T）等位基因的频率解释。因此，临床医生应该认识到，尽管在人群水平上，VKORC 1对剂量需求的贡献在白人中高于非白人;基因型预测不同种族群体的剂量需求相似。（血。2010; 115（18）：3827-3834）
Warfarin-dosing algorithms incorporating CYP2C9 and VKORC1 -1639G> A improve dose prediction compared with algorithms based solely on clinical and demographic factors. However, these algorithms better capture dose variability among whites than Asians or blacks. Herein, we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1 -1639G>A among Asians (n = 1103), blacks (n = 670), and whites (n = 3113). Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 single nucleotide polymorphisms (SNPs) and haplotypes on warfarin dose used both univariate and multi-variable linear regression. VKORC1 -1639G>A and 1173C>T individually explained the greatest variance in dose in all 3 racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction. VKORC1 explained greater variability in dose among whites than blacks and Asians. Differences in the percentage of variance in dose explained by VKORC1 across race were largely accounted for by the frequency of the -1639A (or 1173T) allele. Thus, clinicians should recognize that, although at a population level, the contribution of VKORC1 toward dose requirements is higher in whites than in nonwhites; genotype predicts similar dose requirements across racial groups. (Blood. 2010; 115(18): 3827-3834)