CYP2C9 GENOTYPE AND LONG TERM WARFARIN DOSE REQUIREMENTS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。Warcantine是长期口服抗凝剂的选择，并被大量患者用于治疗或预防血栓形成。细胞色素P450酶CYP 2C 9的活性主要负责华法林的代谢和清除。最近已经鉴定了许多CYP 2C 9多态性，并且与酶活性的实质性差异相关。本提案的目的是确定这种CYP 2C 9多态性是否会影响UTMB抗凝门诊随访的非卧床患者维持稳定抗凝所需的华法林剂量。 待检验的假设是，对华法林治疗更敏感的个体将是具有低活性CYP 2C 9 *2和CYP 2C 9 *3等位基因变体的个体（慢代谢者）。 该研究将招募250名患者，其中125名患者需要每日3 mg华法林。将对所有患者进行CYP 2C 9多态性基因分型，并确定两个队列中三种等位基因变体的患病率。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代谢的差异，而不是药物作用的差异。对于华法林水平意外升高或降低的患者，将进一步检查可能混淆CYP 2C 9基因型与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治疗的患者的结局具有重要意义，并说明了一个潜在的重要例子，即药物遗传学差异的知识可以提高患者的护理。

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.