A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity
A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity
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DOI：
10.1093/hmg/ddi180
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发表时间：
2005-07-01
影响因子：
3.5
通讯作者：
Chen, YT
中科院分区：
文献类型：
--
作者：
Yuan, HY;Chen, JJ;Chen, YT
Warcantine是一种常用的抗凝剂，其抗凝作用所需的剂量在个体间和种族间存在较大差异。亚洲人群（包括中国人）需要的维持剂量比高加索人低得多，其机制仍不清楚。我们测定了16例华法林敏感的中国患者（≥ 6.0 mg/d，n = 5）、104例随机选择的接受华法林治疗的中国患者、95例正常中国对照和92例正常高加索人的CYP 2C 9和VKORC 1的DNA序列变异。我们在4例华法林敏感患者中鉴定了3种CYP 2C 9变异体，即CYP 2C 9 *3、T299 A和P382 L。在所有华法林敏感的患者中发现了一种新的VKORC 1启动子多态性（-1639 G > A），以纯合形式（基因型AA）呈现。耐药患者为AG或GG。在随机选择的104例接受华法林治疗的中国患者中，AA基因型患者的华法林剂量也低于AG/GG基因型患者（P < 0.0001）。中国华法林患者AA、AG和GG基因型频率分别为79.7%、17.6%和2.7%，与正常对照组（82%、18%和0%）相似，但与白种人（14%、47%和39%）差异有统计学意义（P < 0.0001）。启动子多态性消除了E-box共有序列，双荧光素酶检测显示，VOKRC 1启动子与G等位基因相比，活性增加了44%。A/G等位基因频率及其VKORC 1启动子活性水平的差异可能强调了华法林剂量的个体间差异以及中国人和白人之间的种族差异。
Warfarin, a commonly prescribed anticoagulant, exhibited large inter-individual and inter-ethnic differences in the dose required for its anticoagulation effect. Asian populations, including Chinese, require a much lower maintenance dose than Caucasians, for which the mechanisms still remain unknown. We determined DNA sequence variants in CYP2C9 and VKORC1 in 16 Chinese patients having warfarin sensitivity (= 6.0 mg/day, n = 5), 104 randomly selected Chinese patients receiving warfarin, 95 normal Chinese controls and 92 normal Caucasians. We identified three CYP2C9 variants, CYP2C9*3, T299A and P382L, in four warfarin-sensitive patients. A novel VKORC1 promoter polymorphism (-1639 G > A) presented in the homozygous form (genotype AA) was found in all warfarin-sensitive patients. The resistant patients were either AG or GG. Among the 104 randomly selected Chinese patients receiving warfarin, AA genotype also had lower dose than the AG/GG genotype (P < 0.0001). Frequencies of AA, AG and GG genotypes were comparable in Chinese patients receiving warfarin (79.7,17.6 and 2.7%) and normal Chinese controls (82,18 and 0%), but differed significantly from Caucasians (14,47 and 39%) (P < 0.0001). The promoter polymorphism abolished the E-box consensus sequences and dual luciferase assay revealed that VOKRC1 promoter with the G allele had a 44% increase of activity when compared with the A allele. The differences in allele frequencies of A/G allele and its levels of VKORC1 promoter activity may underscore the inter-individual differences in warfarin dosage as well as inter-ethnic differences between Chinese and Caucasians.