CYP2C9 Haplotype Structure in European American Warfarin Patients and Association with Clinical Outcomes
CYP2C9 Haplotype Structure in European American Warfarin Patients and Association with Clinical Outcomes
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DOI：
10.1016/j.clpt.2005.01.019
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发表时间：
2005-05
影响因子：
6.7
通讯作者：
D. Veenstra;D. Blough;M. Higashi;F. Farin;Sengkeo Srinouanprachan;M. Rieder;A. Rettie
中科院分区：
文献类型：
--
作者：
D. Veenstra;D. Blough;M. Higashi;F. Farin;Sengkeo Srinouanprachan;M. Rieder;A. Rettie
本研究的目的是确定欧美人群中细胞色素P450 (CYP) 2C9基因的单倍型结构，并评估encyp2c9单倍型与抗凝相关结果之间的关系。方法对192例接受华法林治疗的欧美患者的基因组脱氧核糖核酸进行重测序，对CYP2C9基因组区域的60000个碱基进行重测序，包括所有外显子，密集采样内含子，5 ' -侧翼区约10000个碱基，3 ' -非翻译区约17000个碱基。结果共检测到132个单核苷酸多态性（snp），其中47个存在于5′侧启动子区，11个存在于外显子编码区，74个存在于内含子区。编码区的9个非同义snp为cyp2c9 *2、*3、*9、*11和*12；R125H;还有3个新的结构变体。在大于5%的小等位基因频率中存在60个snp，从该亚群中推断出23个单倍型。聚类分析确定了6个主要的相关单倍型类群，进一步命名为1A、1B、1C、1D、2或3。*2和* 3snp仅出现在2组和3组，这两组联合使用华法林维持剂量显著降低，给药稳定时间延长，出血风险增加。相比之下，单倍型1A、1B、1C和1D的组合与这些结果的差异无关。这些数据在欧美患者群体中建立了一个全基因、高分辨率的cyp2c9单倍型结构，并表明外显子的遗传变异，而不是启动子或其他调控区域，是该人群中与cyp2c9变异相关的华法林敏感性的主要原因。临床药理学与治疗学（2005）77,353-364；doi: 10.1016 / j.clpt.2005.01.019
ObjectiveThe goal of this study was to define the haplotype structure of the cytochrome P450 (CYP) 2C9 gene in a European American population and evaluate associations betweenCYP2C9haplotypes and anticoagulation‐related outcomes.MethodsGenomic deoxyribonucleic acid from 192 European American patients stabilized on warfarin therapy was resequenced across 60 kilobases of the CYP2C9 genomic region, including all exons, dense sampling of introns, approximately 10 kilobases of the 5′‐flanking region, and approximately 1.7 kilobases of the 3′‐untranslated region.ResultsA total of 132 single nucleotide polymorphisms (SNPs) were detected, of which 47 were present in the 5′‐flanking promoter region, 11 in the exonic coding region, and 74 in the intron regions. Nine nonsynonymous SNPs in the coding region consisted ofCYP2C9*2,*3,*9,*11, and*12; R125H; and 3 new structural variants. Sixty SNPs were present at a minor allele frequency of greater than 5%, and from this subpopulation, 23 haplotypes were inferred. Clustering analysis identified 6 major groups of related haplotypes that were further designated 1A, 1B, 1C, 1D, 2, or 3. The*2and*3SNPs appeared exclusively in groups 2 and 3, and these groups combined were associated with significantly reduced warfarin maintenance doses, longer time to stable dosing, and increased risk of bleeding. In contrast, combinations of haplotypes 1A, 1B, 1C, and 1D were not associated with differences in any of these outcomes.ConclusionThese data establish a whole‐gene, high‐resolution haplotype structure forCYP2C9in a European American patient population and suggest that genetic variation in exons, rather than the promoter or other regulatory regions, is largely responsible for warfarin sensitivity associated withCYP2C9variants in this population.Clinical Pharmacology & Therapeutics(2005)77, 353–364; doi: 10.1016/j.clpt.2005.01.019