title: Pharmacogenomics of warfarin dose requirements in Hispanics.
abstract: While Hispanics are the largest and most rapidly growing minority population in the United States, they are underrepresented in pharmacogenomic studies with warfarin. We sought to determine the combination of clinical and genetic influences of warfarin dose requirements in Hispanics. In addition, we tested the performance of published warfarin dosing algorithms derived from largely non-Hispanic cohorts in an inner-city U.S. Hispanic population. Genetic samples and clinical data were obtained from 50 Hispanics on a stable dose of warfarin. The contribution of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex-1 (VKORC1) genotypes and clinical factors to warfarin dose requirements was determined. The correlation between the predicted dose using published algorithms and therapeutic dose was also assessed. Compared to the VKORC1-1639 GG genotype, warfarin dose requirements were 30% and 62% lower with the GA and AA genotypes, respectively (p=0.001). The combination of the VKORC1-1639G>A and CYP2C9 genotypes and clinical factors explained 56% of the inter-patient variability in warfarin dose. Warfarin dose predicted using algorithms derived from mostly non-Hispanic cohorts was significantly correlated with the therapeutic dose in our Hispanic cohort (r(2)=0.43 to 0.49; p<0.001); the predicted dose was within 1.0 mg/day of the therapeutic dose for 40% to 50% of patients. Our data suggest that factors influencing warfarin dose requirements in Hispanic Caucasians are similar to those previously described in European Caucasians and that dosing algorithms derived from non-Hispanic Caucasian cohorts are applicable to Hispanics living in the U.S.
authors.affiliation: Department of Pharmacy Practice, College of Pharmacy, 833 S. Wood St, Chicago, IL 60612, USA. humma@uic.edu
authors.forename: Larisa H
authors.initials: LH
authors.lastname: Cavallari
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Momary
authors.forename: Shitalben R
authors.initials: SR
authors.lastname: Patel
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Shapiro
authors.forename: Edith
authors.initials: E
authors.lastname: Nutescu
authors.forename: Marlos A G
authors.initials: MA
authors.lastname: Viana
mesh_terms: D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D005260:Female; D005838:Genotype; D006630:Hispanic or Latino / Q000208:ethnology / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D014481:United States; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage / Q000627:therapeutic use; D044465:White People / Q000208:ethnology / Q000235:genetics
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases