VKORC1 polymorphisms, haplotypes and haplotype groups on warfarin dose among African-Americans and European-Americans.
VKORC1 polymorphisms, haplotypes and haplotype groups on warfarin dose among African-Americans and European-Americans.
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DOI：
10.2217/14622416.9.10.1445
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发表时间：
2008-10
期刊：
影响因子：
2.1
通讯作者：
Liu N
中科院分区：
文献类型：
--
作者：
Limdi NA;Beasley TM;Crowley MR;Goldstein JA;Rieder MJ;Flockhart DA;Arnett DK;Acton RT;Liu N
虽然已经研究了VKORC 1和CYP2C9多态性对华法林反应的影响，但与欧洲裔美国人相比，非裔美国人中CYP2C9和VKORC 1解释的剂量变异性较低。这导致研究者假设，VKORC 1单倍型的评估可能有助于捕获更大比例的剂量变异性，这一代表性不足的群体。然而，非洲裔美国人的代表性不足和一些VKORC1多态性的评估阻碍了这一努力。为了确定VKORC 1单倍型或单倍型组是否解释华法林剂量的较高变异性，我们全面评估了273名非洲裔美国人和302名欧洲裔美国人的VKORC 1多态性。考虑CYP2C9（*2、*3、*5、*6和 *11）和临床协变量后，在人种分层多变量分析中评价VKORC 1多态性、人种特异性单倍型和单倍型组对华法林剂量的影响。VKORC 1解释了欧洲裔美国人中华法林剂量的18%（30%，CYP2C9）变异性，非洲裔美国人中为5%（8%，CYP2C9）。在欧洲裔美国人和12个非洲裔美国人的常见单倍型被确定。在每个人种中，VKORC 1单倍型出现在两个组中：低剂量组（A组）和高剂量组（B组）。与欧洲裔美国人（35%，p < 0.0001）相比，非洲裔美国人的A组单倍型频率较低（10.6%）。VKORC 1单倍型或单倍型组解释的剂量变异性与单一信息多态性相似。我们的研究结果支持使用CYP2C9，VKORC1多态性（rs9934438或rs9923231）和临床协变量来预测非洲裔和欧洲裔美国人的华法林剂量。CYP 2C 9和VKORC 1中一组统一的常见多态性以及有限的临床协变量可用于改善种族多元化人群的华法林剂量预测。
Although the influence of VKORC1 and CYP2C9 polymorphisms on warfarin response has been studied, variability in dose explained by CYP2C9 and VKORC1 is lower among African–Americans compared with European–Americans. This has lead investigators to hypothesize that assessment of VKORC1 haplotypes may help capture a greater proportion of the variability in dose for this under-represented group. However, the inadequate representation of African–Americans and the assessment of a few VKORC1 polymorphisms have hindered this effort. To determine if VKORC1 haplotypes or haplotype groups explain a higher variability in warfarin dose, we comprehensively assessed VKORC1 polymorphisms in 273 African–Americans and 302 European–Americans. The influence of VKORC1 polymorphisms, race-specific haplotypes and haplotype groups on warfarin dose was evaluated in race-stratified multivariable analyses after accounting for CYP2C9 (*2, *3, *5, *6 and *11) and clinical covariates. VKORC1 explained 18% (30% with CYP2C9) variability in warfarin dose among European–Americans and 5% (8% with CYP2C9) among African–Americans. Four common haplotypes in European–Americans and twelve in African–Americans were identified. In each race VKORC1 haplotypes emerged into two groups: low-dose (Group A) and high-dose (Group B). African–Americans had a lower frequency of Group A haplotype (10.6%) compared with European–Americans (35%, p < 0.0001).The variability in dose explained by VKORC1 haplotype or haplotype groups was similar to that of a single informative polymorphism. Our findings support the use of CYP2C9, VKORC1 polymorphisms (rs9934438 or rs9923231) and clinical covariates to predict warfarin dose in both African– and European–Americans. A uniform set of common polymorphisms in CYP2C9 and VKORC1, and limited clinical covariates can be used to improve warfarin dose prediction for a racially diverse population.
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