Divisão de Farmacologia, Coordenação de Pesquisa, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
Br J Clin Pharmacol. 2013 Feb;75(2):334-46. doi: 10.1111/j.1365-2125.2012.04354.x.
Warfarin is the most commonly prescribed oral anticoagulant worldwide despite its narrow therapeutic index and the notorious inter- and intra-individual variability in dose required for the target clinical effect. Pharmacogenetic polymorphisms are major determinants of warfarin pharmacokinetic and dynamics and included in several warfarin dosing algorithms. This review focuses on warfarin pharmacogenomics in sub-Saharan peoples, African Americans and admixed Brazilians. These 'Black' populations differ in several aspects, notably their extent of recent admixture with Europeans, a factor which impacts on the frequency distribution of pharmacogenomic polymorphisms relevant to warfarin dose requirement for the target clinical effect. Whereas a small number of polymorphisms in VKORC1 (3673G > A, rs9923231), CYP2C9 (alleles *2 and *3, rs1799853 and rs1057910, respectively) and arguably CYP4F2 (rs2108622), may capture most of the pharmacogenomic influence on warfarin dose variance in White populations, additional polymorphisms in these, and in other, genes (e.g. CALU rs339097) increase the predictive power of pharmacogenetic warfarin dosing algorithms in the Black populations examined. A personalized strategy for initiation of warfarin therapy, allowing for improved safety and cost-effectiveness for populations of African descent must take into account their pharmacogenomic diversity, as well as socio-economical, cultural and medical factors. Accounting for this heterogeneity in algorithms that are 'friendly' enough to be adopted by warfarin prescribers worldwide requires gathering information from trials at different population levels, but demands also a critical appraisal of racial/ethnic labels that are commonly used in the clinical pharmacology literature but do not accurately reflect genetic ancestry and population diversity.
华法林是全球最常用的口服抗凝药物,尽管其治疗指数较窄,且所需剂量在个体间和个体内存在显著差异。药物遗传学多态性是华法林药代动力学和药效学的主要决定因素,已被纳入几种华法林剂量算法中。本综述重点介绍了撒哈拉以南非洲人、非裔美国人和混合裔巴西人的华法林药物基因组学。这些“黑人”群体在多个方面存在差异,尤其是其与欧洲人的近期混合程度不同,这一因素影响与达到目标临床效果所需的华法林剂量相关的药物基因组学多态性的频率分布。尽管 VKORC1(3673G > A,rs9923231)、CYP2C9(等位基因2 和3,rs1799853 和 rs1057910)和 CYP4F2(rs2108622)中的少数几个多态性可能捕获了华法林剂量变异的药物基因组学影响,但这些基因(如 CALU rs339097)和其他基因中的额外多态性增加了药物基因组学华法林剂量算法在研究的黑人人群中的预测能力。为改善非裔人群的安全性和成本效益,必须针对起始华法林治疗制定个体化策略,充分考虑其药物基因组多样性,以及社会经济、文化和医疗因素。要在足够友好的算法中考虑这种异质性,以便在全球范围内被华法林开处方者采用,需要从不同人群水平的试验中收集信息,但也需要对临床药理学文献中常用的种族/民族标签进行批判性评估,这些标签不能准确反映遗传血统和人群多样性。