The association of CYP2C9 and VKORC1 1173C/T genotype and risk of hemorrhage among African Americans and European Americans is presented. This association was evaluated using Cox proportional hazard regression with adjustment for demographics, comorbidity, and time-varying covariates. Forty-four major and 203 minor hemorrhages occurred over 555 person-years among 446 patients (60.67±15.6 years, 50% men, 227 African Americans). The variant CYP2C9 genotype conferred an increased risk for major (hazard ratio (HR) 3.0; 95% confidence interval (CI): 1.1-8.0) but not minor (HR 1.3; 95% CI: 0.8-2.1) hemorrhage. The risk of major hemorrhage was 5.3-fold (95% CI: 0.4-64.0) higher before stabilization of therapy, 2.2-fold (95% CI: 0.7-6.5) after stabilization, and 2.4-fold (95% CI: 0.8-7.4) during all periods when anticoagulation was not stable. The variant VKORC1 1173C/T genotype did not confer a significant increase in risk for major (HR 1.7; 95% CI: 0.7-4.4) or minor (HR 0.8; 95% CI: 0.5-1.3) hemorrhage. The variant CYP2C9 genotype is associated with an increased risk of major hemorrhage, which persists even after stabilization of therapy.Thromboembolic disorders are significant contributors to morbidity and mortality. 1 Although the efficacy of warfarin in the treatment and prevention of thromboembolic disorders is proven, 2-4 it is vastly underutilized, 5,6 with difficulties in management 5,7 and risk of complications being the main deterrents. 7,8 Recognition of genetic regulation of warfarin response has fueled Correspondence: NA Limdi (E-mail: nlimdi@uab.edu). CONFLICT OF INTERESTThe authors declared no conflict of interest. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript efforts aimed at quantifying this influence, but past efforts have focused on a few cytochrome P450 2C9 (CYP2C9) alleles in largely white populations. 9-13 Outcome definitions varied significantly, with several studies addressing risk of over-anticoagulation, 12,13 whereas others analyzed hemorrhagic complications retrospectively. 9-11 Exclusion of underrepresented ethnic groups and inability to address factors such as concurrent medications and comorbid conditions 9-13 limit the generalizability of study results. Although these studies have enhanced our understanding of the association of CYP2C9 and hemorrhagic complications, a prospective study in racially representative population is lacking. A recent report indicates the significance of 1173C/T polymorphism in the vitamin K epoxide reductase complex 1 (VKORC1) gene in explaining variability in warfarin dose requirements among both European-American and African-American patients. 14 However, the influence of VKORC1 polymorphisms in risk of hemorrhagic complications is lacking.Herein we present the association of CYP2C9 and VKORC1 1173C/T (rs9934438) genotypes and risk of hemorrhagic complications among African Americans and European Americans on warfarin therapy. RESULTSAll patients meeting eligibility criteria (n=526) were asked to particip...

Background-Although multiple reports have documented the influence of CYP2C9 and VKORC1 variantson warfarin dose, risk of over-anticoagulation and hemorrhage, their influence on anticoagulation maintenance and individual proportion of time spent in target INR range (PPTR) is limited. Moreover the potential benefit of genotype-guided dosing implemented after initiation of therapy in a racially diverse population has not been explored. Herein we present the influence of CYP2C9 and VKORC1 C1173T on warfarin response during the first 30 days of therapy.

Background-Cytochrome P4502C9 (CYP2C9) plays a vital role in drug metabolism. There has been an increased effort to identify polymorphisms within the gene and determine their clinical consequences. However, most of these efforts have focused on populations of European descent. Herein we report the influence of CYP2C9 genotype on warfarin dose among European American and African American patients. We also identify two new mutations; one in the coding region and one in the non-coding region of the CYP2C9 gene.