title: Effect of NQO1 and CYP4F2 genotypes on warfarin dose requirements in Hispanic-Americans and African-Americans.
abstract: OBJECTIVE
  The objective of this study was to determine the additional contribution of NQO1 and CYP4F2 genotypes to warfarin dose requirements across two racial groups after accounting for known clinical and genetic predictors.
  
  
  METHODS
  The following were assessed in a cohort of 260 African-Americans and 53 Hispanic-Americans: clinical data; NQO1 p.P187S (*1/*2); CYP2C9*2, *3, *5, *6, *8 and *11; CYP4F2 p.V433M; and VKORC1 c.-1639G>A genotypes.
  
  
  RESULTS
  Both the CYP4F2 433M (0.23 vs 0.06; p < 0.05) and NQO1*2 (0.27 vs 0.18; p < 0.05) allele frequencies were higher in Hispanic-Americans compared with African-Americans. Multiple regression analysis in the Hispanic-American cohort revealed that each CYP4F2 433M allele was associated with a 22% increase in warfarin maintenance dose (p = 0.019). Possession of the NQO1*2 allele was associated with a 34% increase in warfarin maintenance dose (p = 0.004), while adjusting for associated genetic (CYP2C9, CYP4F2 and VKORC1) and clinical factors. In this population, the inclusion of CYP4F2 and NQO1*2 genotypes improved the dose variability explained by the model from 0.58 to 0.68 (p = 0.001), a 17% relative improvement. By contrast, there was no association between CYP4F2 or NQO1*2 genotype and therapeutic warfarin dose in African-Americans after adjusting for known genetic and clinical predictors.
  
  
  CONCLUSIONS
  In our cohort of inner-city Hispanic-Americans, the CYP4F2 and NQO1*2 genotypes significantly contributed to warfarin dose requirements. If our findings are confirmed, they would suggest that inclusion of the CYP4F2 and NQO1*2 genotypes in warfarin dose prediction algorithms may improve the predictive ability of such algorithms in Hispanic-Americans.
authors.affiliation: Department of Pharmacy Practice, University of Illinois at Chicago, 833 S Wood St, Rm 164, Chicago, IL 60612-7230, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Bress
authors.forename: Shitalben R
authors.initials: SR
authors.lastname: Patel
authors.forename: Minoli A
authors.initials: MA
authors.lastname: Perera
authors.forename: Richard T
authors.initials: RT
authors.lastname: Campbell
authors.forename: Rick A
authors.initials: RA
authors.lastname: Kittles
authors.forename: Larisa H
authors.initials: LH
authors.lastname: Cavallari
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human