Institute of Cellular Medicine, Newcastle University Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
Genome Med. 2009 Jan 21;1(1):10. doi: 10.1186/gm10.
Warfarin and other coumarin anticoagulants are widely used clinically, but currently dosing is determined individually on the basis of patient response. There is increasing evidence that genetic factors, together with several non-genetic patient-specific factors, are important determinants of stable dose requirement for these compounds. Genotype for CYP2C9, which encodes the main cytochrome P450 enzyme that metabolizes warfarin, and VKORC1, the gene encoding the warfarin target vitamin K epoxide reductase, together account for approximately 30% of the variability in dose requirement. The past two years have seen several advances in the area of genetic factors affecting coumarin anticoagulant response. In particular, prospective studies have taken place to analyze whether earlier small retrospective studies can be confirmed, and the question of whether genes other than CYP2C9 and VKORC1 are important in determining dose requirement has been examined. So far, no strong evidence that other genes contribute to dose requirement has been found, apart from a minor but novel role for another cytochrome P450 gene, CYP4F2. A recently published whole genome association study confirms that the main genes important in warfarin response are CYP2C9 and VKORC1. Clinical trials comparing genotype-guided and conventional warfarin initiation have suggested that genotyping may be of value, but larger studies are still needed to show clear clinical benefit. Current knowledge of genetic factors affecting other coumarin anticoagulants is more limited and this area requires further study, as does the impact of ethnic variation in genes relevant to coumarin responses. Here we review recent advances in the area of coumarin anticoagulant genetics and its potential clinical application.
华法林和其他香豆素类抗凝剂在临床上被广泛应用，但目前的剂量是根据患者的反应来确定的。越来越多的证据表明，遗传因素以及几个非遗传的患者特定因素是这些化合物稳定剂量需求的重要决定因素。编码主要代谢华法林的细胞色素 P450 酶 CYP2C9 的基因，以及编码华法林靶标维生素 K 环氧化物还原酶的 VKORC1 基因，共同解释了这些化合物剂量需求的大约 30%的可变性。在过去的两年中，遗传因素影响香豆素类抗凝剂反应的领域取得了一些进展。特别是进行了一些前瞻性研究，以分析早期的小型回顾性研究是否可以得到证实，以及 CYP2C9 和 VKORC1 以外的基因是否对确定剂量需求很重要的问题进行了研究。到目前为止，除了另一个细胞色素 P450 基因 CYP4F2 具有较小但新颖的作用外，尚未发现其他基因对剂量需求有重要贡献的强有力证据。最近发表的全基因组关联研究证实，在华法林反应中起主要作用的基因是 CYP2C9 和 VKORC1。比较基因型指导和常规华法林起始的临床试验表明，基因分型可能具有一定的价值，但仍需要更大的研究来显示明确的临床益处。目前对影响其他香豆素类抗凝剂的遗传因素的了解更为有限，这一领域需要进一步研究，以及与香豆素反应相关的基因的种族差异的影响也需要进一步研究。在这里，我们综述了香豆素类抗凝剂遗传学领域的最新进展及其潜在的临床应用。
