Influence of CYP2C9 genotype on warfarin dose among African-Americans and European-Americans
Influence of CYP2C9 genotype on warfarin dose among African-Americans and European-Americans
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DOI：
10.2217/17410541.4.2.157
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发表时间：
2007-05-01
影响因子：
2.3
通讯作者：
Acton, R. T.
中科院分区：
文献类型：
--
作者：
Limdi, Nita A.;Goldstein, J. A.;Acton, R. T.
背景：细胞色素P450（CYP）2C 9在药物代谢中起重要作用。已经有越来越多的努力，以确定基因内的多态性，并确定其临床后果。然而，这些努力大多侧重于欧洲裔人口。在此，我们报告了CYP 2C 9基因型对欧洲裔美国人和非洲裔美国人患者华法林剂量的影响。我们还确定了两个新的突变，一个在编码区和一个在非编码区的CYP 2C 9 gene.Methods：患者（年龄>20岁）后，获得医疗，生活方式和伴随用药史。记录国际标准化比值、华法林剂量、合并用药、饮食、体力活动和并发症发生率的变化。采用限制性片段长度多态性PCR和焦磷酸测序确定CYP 2C 9基因型。基因型频率和Hardy-Weinberg平衡假设的差异使用卡方（2）统计和精确检验进行评估。使用多变量线性regression.Results：本报告包括490例患者（平均年龄：60.6 +/- 15.6岁; 51.3%男性）的基因型剂量协会进行了评估。非裔美国患者占队列的48.9%，平均随访时间为13.5（+/- 10.6）个月。与非洲裔美国人（1.1%和1.8%）相比，欧洲裔美国人（分别为11.24%和5.1%）的CYP 2C 9 *2和 *3等位基因更常见。仅在非洲裔美国人中观察到CYP 2C 9 *5（0.9%）、*6（0.4%）和 *11（1.1%）变异体。与非洲裔美国人相比，欧洲裔美国人的变异基因型更常见（29.8% vs 9.73%; p < 0.0001）。在单变量和多变量分析中，华法林剂量与CYP 2C 9基因型显著相关（p < 0.0001）。多变量种族特异性分析突出了CYP 2C 9基因型在欧洲-美国人中的贡献，但在非洲-美国patient.Conclusion：变异CYP 2C 9基因型是更常见的欧洲-美国人相比，非洲-美国人。在非洲裔美国人中，变异基因型频率高于先前报道的频率。CYP 2C 9基因型可预测欧洲裔美国人的华法林剂量，但不能预测非洲裔美国人。
Background: Cytochrome P450 (CYP)2C9 plays a vital role in drug metabolism. There has been an increased effort to identify polymorphisms within the gene and to determine their clinical consequences. However, most of these efforts have focused on populations of European descent. Herein we report the influence of CYP2C9 genotype on warfarin dose among European-American and African-American patients. We also identify two new mutations, one in the coding region and one in the noncoding region of the CYP2C9 gene.Methods: Patients (aged >20 years) were enrolled after obtaining medical, lifestyle and concomitant medication history. Changes in international normalized ratio, warfarin dose, co-medications, diet, physical activity and the occurrence of complications were documented. CYP2C9 genotype was determined using PCR with restriction fragment length polymorphisms, and pyrosequencing. Differences in genotype frequencies and Hardy-Weinberg equilibrium assumptions were assessed using chi(2) statistics and exact tests. The genotype-dose association was evaluated using multivariable linear regression.Results: This report includes 490 patients (mean age: 60.6 +/- 15.6 years; 51.3% men). African-American patients comprised 48.9% of the cohort, with a mean follow-up of 13.5 (+/- 10.6) months. Both the CYP2C9*2 and *3 allele were more frequent in European-Americans (11.24 and 5.1%, respectively) compared with African-Americans (1.1 and 1.8%). CYP2C9*5 (0.9%), *6 (0.4%) and *11 (1.1%) variants were only observed in African-Americans. The variant genotype is more frequent among European-Americans compared with African-Americans (29.8 vs 9.73%; p < 0.0001). Warfarin dose was significantly related to CYP2C9 genotype (p < 0.0001), both in univariate and multivariate analyses. Multivariable race-specific analyses highlight the contribution of CYP2C9 genotype among European-American but not among African-American patients.Conclusion: The variant CYP2C9 genotype is more frequent among European-Americans compared with African-Americans. Among African-Americans the variant genotype frequency is higher than previously reported. CYP2C9 genotype predicts warfarin dose in European-Americans, but not in African-Americans.