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.
Showing the most recent 10 out of 465 publications
