University of North Carolina, Chapel Hill, 5039 Old Clinic Building, Campus Box 7110, Chapel Hill, NC 27599, USA.
Trends Pharmacol Sci. 2009 Jul;30(7):375-86. doi: 10.1016/j.tips.2009.05.001. Epub 2009 Jun 17.
Warfarin has a narrow therapeutic window and the hemorrhagic or thrombotic implications of over- or under-dosing can be devastating. Moreover, there is substantial individual variation in response to warfarin. This review describes the genetic and clinical factors associated with warfarin dosing, including recent developments. The pivotal role of CYP2C9 and VKORC1 is emphasized because polymorphisms of these two genes account for approximately 40% of the variation in dose requirements. Recent studies have reported that polymorphisms in CYP4F2 might account for between 2 and 7% of the variation. Large studies published recently, including the Warfarin Genetics (WARG) study and the International Warfarin Pharmacogenetic Consortium, have added to our understanding of factors relating to warfarin dosing. Several prospective studies have evaluated genotype-guided dosing, but these have found negative results or were poorly designed. Whether genotype-guided dosing is clinically beneficial remains unclear, but studies are currently underway that will help to determine this.
华法林的治疗窗较窄，剂量过大或过小都可能导致出血或血栓形成，后果严重。此外，个体对华法林的反应存在很大差异。本文综述了与华法林剂量相关的遗传和临床因素，包括最新进展。重点介绍 CYP2C9 和 VKORC1 的关键作用，因为这两个基因的多态性大约解释了剂量需求变化的 40%。最近的研究报告称，CYP4F2 的多态性可能占变化的 2%至 7%。最近发表的大型研究，包括华法林遗传学（WARG）研究和国际华法林药物基因组学联合会，加深了我们对华法林剂量相关因素的认识。几项前瞻性研究评估了基于基因型的剂量调整，但结果为阴性或设计不佳。基于基因型的剂量调整是否具有临床获益尚不清楚，但目前正在进行相关研究以确定这一点。
