Aithal G P, Day C P, Kesteven P J, Daly A K
Department of Medicine, University of Newcastle upon Tyne Medical School, UK.
Lancet. 1999 Feb 27;353(9154):717-9. doi: 10.1016/S0140-6736(98)04474-2.
The cytochrome P450 CYP2C9 is responsible for the metabolism of S-warfarin. Two known allelic variants CYP2C92 and CYP2C93 differ from the wild type CYP2C9*1 by a single aminoacid substitution in each case. The allelic variants are associated with impaired hydroxylation of S-warfarin in in-vitro expression systems. We have studied the effect of CYP2C9 polymorphism on the in-vivo warfarin dose requirement.
Patients with a daily warfarin dose requirement of 1.5 mg or less (low-dose group, n=36), randomly selected patients with a wide range of dose requirements from an anticoagulant clinic in north-east England (clinic control group, n=52), and 100 healthy controls from the community in the same region were studied. Genotyping for the CYP2C92 and CYP2C93 alleles was done by PCR analysis. Case notes were reviewed to assess the difficulties encountered during the induction of warfarin therapy and bleeding complications in the low-dose and clinic control groups.
The odds ratio for individuals with a low warfarin dose requirement having one or more CYP2C9 variant alleles compared with the normal population was 6.21 (95% CI 2.48-15.6). Patients in the low-dose group were more likely to have difficulties at the time of induction of warfarin therapy (5.97 [2.26-15.82]) and have increased risk of major bleeding complications (rate ratio 3.68 [1.43-9.50]) when compared with randomly selected clinic controls.
We have shown that there is a strong association between CYP2C9 variant alleles and low warfarin dose requirement. CYP2C9 genotyping may identify a subgroup of patients who have difficulty at induction of warfarin therapy and are potentially at a higher risk of bleeding complications.
细胞色素P450 CYP2C9负责S-华法林的代谢。两种已知的等位基因变体CYP2C92和CYP2C93在每种情况下均与野生型CYP2C9*1存在单个氨基酸取代差异。这些等位基因变体与体外表达系统中S-华法林的羟基化受损有关。我们研究了CYP2C9基因多态性对体内华法林剂量需求的影响。
研究了每日华法林剂量需求为1.5mg或更低的患者（低剂量组，n = 36）、从英格兰东北部一家抗凝门诊随机选择的具有广泛剂量需求的患者（门诊对照组，n = 52）以及来自同一地区社区的100名健康对照者。通过PCR分析对CYP2C92和CYP2C93等位基因进行基因分型。回顾病例记录以评估低剂量组和门诊对照组在华法林治疗诱导期间遇到的困难以及出血并发症情况。
与正常人群相比，华法林剂量需求低且具有一个或多个CYP2C9变体等位基因的个体的优势比为6.21（95%可信区间2.48 - 15.6）。与随机选择的门诊对照组相比，低剂量组患者在华法林治疗诱导时更可能遇到困难（5.97 [2.26 - 15.82]），且发生大出血并发症的风险增加（率比3.68 [1.43 - 9.50]）。
我们已表明CYP2C9变体等位基因与低华法林剂量需求之间存在强关联。CYP2C9基因分型可能识别出在华法林治疗诱导时存在困难且潜在出血并发症风险较高的患者亚组。
