CYP2C9 promoter region single-nucleotide polymorphisms linked to the R150H polymorphism are functional suggesting their role in CYP2C9*8-mediated effects.
CYP2C9 promoter region single-nucleotide polymorphisms linked to the R150H polymorphism are functional suggesting their role in CYP2C9*8-mediated effects.
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DOI：
10.1097/fpc.0b013e32835e95c7
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发表时间：
2013-04
影响因子：
2.6
通讯作者：
Jeong H
中科院分区：
文献类型：
--
作者：
Cavallari LH;Vaynshteyn D;Freeman KM;Wang D;Perera MA;Takahashi H;Drozda K;Patel SR;Jeong H
细胞色素 P450 2C9 (CYP2C9) c.449G> A (*8) 在非裔美国人中很常见，与华法林清除率降低有关。我们检查了 449G > A 遗传的启动子区域变异对华法林清除率、剂量要求和 CYP2C9 表达的影响。在非裔美国人队列中，449G > A 与 c 存在连锁不平衡。 – 1766T >C (r2 = 0.89) 和 c。 – 1188T>C (D′ =1)。 – 1766C 和 449A 等位基因与 – 1188CC 基因型的组合与较低的 S-华法林清除率相关（0.86±0.22 对比 1.66±0.75 ml/min/m2；n=48；P <0.01）和剂量要求 [33 (25–49) 对比 43 (35–56) mg/周； n = 243； P=0.03]与其他基因型相比。在肝组织中，与参考等位基因相比，具有 – 1766C/ – 1188C/449A 单倍型的等位基因的 mRNA 表达量降低两倍。在启动子报告基因检测中，–1766C/–1188C 单倍型降低了 CYP2C9 启动子活性。这些数据表明，449G >A 遗传的启动子区域多态性会降低 CYP2C9 表达，并导致 CYP2C9*8 对华法林清除率和剂量需求的影响。
Cytochrome P450 2C9 (CYP2C9) c.449G> A (*8) is common in African Americans and is associated with decreased warfarin clearance. We examined the effect of promoter region variants inherited with 449G > A on warfarin clearance, dose requirements, and CYP2C9 expression. In an African American cohort, 449G > A was in linkage disequilibrium with c. – 1766T >C (r2 = 0.89) and c. – 1188T>C (D′ =1). The combination of the – 1766C and 449A alleles with the – 1188CC genotype was associated with lower S-warfarin clearance (0.86±0.22 vs. 1.66±0.75 ml/min/m2; n=48; P <0.01) and dose requirements [33 (25–49) vs. 43 (35–56) mg/week; n= 243; P= 0.03] compared with other genotypes. In liver tissue, alleles with the – 1766C/ – 1188C/449A haplotype showed two-fold decreased mRNA expression compared with reference alleles. In a promoter reporter assay, the – 1766C/ – 1188C haplotype decreased CYP2C9 promoter activity. These data suggest that promoter region polymorphisms inherited with 449G >A decrease CYP2C9 expression and contribute to CYP2C9*8 effects on warfarin clearance and dose requirements.