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.
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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...