CYP2C9 GENOTYPE AND LONG TERM WARFARIN DOSE REQUIREMENTS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。华法林是长期口服抗凝剂的选择，并被开给大量患者治疗或预防血栓形成。细胞色素P450酶的活性主要负责华法林的代谢和清除。最近发现了许多与酶活性显著不同有关的细胞色素P450 2 C9基因多态性。这项建议的目的是确定这种CYP2C9基因多态性是否会影响UTMB抗凝诊所门诊患者维持稳定抗凝所需的华法林剂量。需要检验的假设是，对华法林治疗更敏感的个体将是那些具有低活性的CYP2C9*2和CYP2C9*3等位基因变异(缓慢代谢物)的人。这项研究将招募250名患者，其中125人每天需要3毫克华法林。所有患者都将接受CYP2C9基因多态的基因分型，并将确定这三个等位基因变异在两个队列中的患病率。将测量华法林水平，预期结果是所有患者的药物水平相似，并确认剂量需求的差异反映了药物新陈代谢的差异，而不是药物作用的差异。华法林水平出乎意料地高或低的患者将接受进一步检查，以寻找可能混淆CYP2C9基因和华法林剂量需求之间假设关系的因素。这项研究对改善需要长期抗凝的患者的预后具有重要意义，并说明了一个潜在的重要例子，即了解药物遗传差异可以加强患者护理。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Warfarin is the long term, oral anticoagulant of choice, and is prescribed to large numbers of patients to treat or prevent thrombosis. Activity of the cytochrome P450 enzyme CYP2C9 is principally responsible for metabolism and clearance of warfarin. A number of CYP2C9 polymorphisms have been identified recently, and are associated with substantial differences in enzyme activity. The goal of this proposal is to determine whether this CYP2C9 polymorphism can affect the dose of warfarin required to maintain stable anticoagulation in ambulatory patients followed in the Anticoagulant Clinic at UTMB. The hypothesis to be tested is that individuals more sensitive to warfarin treatment will be those with the low activity CYP2C9*2 and CYP2C9*3 allelic variants (slow metabolizers). The study will enroll 250 patients, 125 of whom require 3mg warfarin daily. All patients wil be genotyped for CYP2C9 polymorphism, and the prevalence of the three allelic variants will be determined in both cohorts. Warfarin levels will be measured with the anticipated result that all patients will have similar drug levels and to confirm that differences in dose requirements reflect a difference in drug metabolism and not drug action. Patients with unexpectedly high or low warfarin levels will be examined further for factors that may confound the hypothesized relationship between CYP2C9genotype and warfarin dose requirement. The study has important implications for improving outcomes of patients who require long term anticoagulation, and illustrates a potentially important example where knowledge of pharmacogenetic differences can enhance patient care.