title: Association of the GGCX (CAA)16/17 repeat polymorphism with higher warfarin dose requirements in African Americans.
abstract: OBJECTIVE
  Little is known about genetic contributors to higher than usual warfarin dose requirements, particularly for African Americans. This study tested the hypothesis that the γ-glutamyl carboxylase (GGCX) genotype contributes to warfarin dose requirements greater than 7.5 mg/day in an African American population.
  
  
  METHODS
  A total of 338 African Americans on a stable dose of warfarin were enrolled. The GGCX rs10654848 (CAA)n, rs12714145 (G>A), and rs699664 (p.R325Q); VKORC1 c.-1639G>A and rs61162043; and CYP2C9*2, *3, *5, *8, *11, and rs7089580 genotypes were tested for their association with dose requirements greater than 7.5 mg/day alone and in the context of other variables known to influence dose variability.
  
  
  RESULTS
  The GGCX rs10654848 (CAA)16 or 17 repeat occurred at a frequency of 2.6% in African Americans and was overrepresented among patients requiring greater than 7.5 mg/day versus those who required lower doses (12 vs. 3%, P=0.003; odds ratio 4.0, 95% confidence interval, 1.5-10.5). The GGCX rs10654848 genotype remained associated with high dose requirements on regression analysis including age, body size, and VKORC1 genotype. On linear regression, the GGCX rs10654848 genotype explained 2% of the overall variability in warfarin dose in African Americans. An examination of the GGCX rs10654848 genotype in warfarin-treated Caucasians revealed a (CAA)16 repeat frequency of only 0.27% (P=0.008 compared with African Americans).
  
  
  CONCLUSIONS
  These data support the GGCX rs10654848 genotype as a predictor of higher than usual warfarin doses in African Americans, who have a 10-fold higher frequency of the (CAA)16/17 repeat compared with Caucasians.
authors.affiliation: Department of Pharmacy Practice, University of Illinois, Chicago, IL 60612-7230, USA. humma@uic.edu
authors.forename: Larisa H
authors.initials: LH
authors.lastname: Cavallari
authors.forename: Minoli
authors.initials: M
authors.lastname: Perera
authors.forename: Mia
authors.initials: M
authors.lastname: Wadelius
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Gelson
authors.initials: G
authors.lastname: Taube
authors.forename: Shitalben R
authors.initials: SR
authors.lastname: Patel
authors.forename: Keston
authors.initials: K
authors.lastname: Aquino-Michaels
authors.forename: Marlos A G
authors.initials: MA
authors.lastname: Viana
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Shapiro
authors.forename: Edith A
authors.initials: EA
authors.lastname: Nutescu
mesh_terms: D001741:Black or African American; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000627:therapeutic use*; D019735:Carbon-Carbon Ligases / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D014859:Warfarin / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase