title: Genetic determinants of variability in warfarin response after the dose-titration phase.
abstract: OBJECTIVE
  Genetic factors contribute considerably toward variability in warfarin dose requirements and are important in the dose-titration phase; their effects on the stability of anticoagulation later in therapy are not known.
  
  
  METHODS
  Using deidentified electronic medical records linked to a DNA-biobank, we studied 140 African-Americans and 943 European-Americans after the warfarin dose-titration phase. We genotyped 12 single nucleotide polymorphisms in genes (CYP2C9, VKORC1, CYP4F2, GGCX, EPHX1, CALU) associated with altered warfarin dose requirements and tested their associations with international normalized ratio variability (INRVAR) and percent time in therapeutic range in European-Americans and African-Americans.
  
  
  RESULTS
  One allele copy of rs2108622 in CYP4F2 was associated with a 15% [95% confidence interval (CI): 1-26, P=0.03] decrease in the median INRVAR in European-Americans. In African-Americans, GGCX variants rs11676382 and rs699664 were associated with 4.16-fold (95% CI: 1.45-11.97, P=0.009) and 1.50-fold (95% CI: 1.07-2.08, P=0.02) changes in the median INRVAR per variant allele copy, respectively; rs11676382 was also significantly associated with a 23.19% (95% CI: 5.89-40.48, P=0.01) decrease in time in therapeutic range. The total variation in INRVAR explained by both clinical factors and rs2108622 was 5.2% for European-Americans. In African-Americans, the inclusion of GGCX variants rs11676382 and rs699664, and the CYP2C9*8 variant rs7900194 explained ∼29% of the variation in INRVAR.
  
  
  CONCLUSIONS
  The stability of anticoagulation after the warfarin dose-titration phase is differentially affected by variants in CYP4F2 in European-Americans and GGCX loci in African-Americans.
authors.affiliation: aDepartment of Medicine, Division of Clinical Pharmacology Departments of bBiostatistics cMedical Bioinformatics dMedicine and Pharmacology eVanderbilt Institute for Clinical & Translational Research, Vanderbilt University School of Medicine, Nashville, Tennessee fDivision of Pharmaceutical Sciences, Fairleigh Dickinson University School of Pharmacy, Florham Park, New Jersey gMedical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Otito F
authors.initials: OF
authors.lastname: Iwuchukwu
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Ramirez
authors.forename: Yaping
authors.initials: Y
authors.lastname: Shi
authors.forename: Erica A
authors.initials: EA
authors.lastname: Bowton
authors.forename: Vivian K
authors.initials: VK
authors.lastname: Kawai
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Schildcrout
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Denny
authors.forename: C Michael
authors.initials: CM
authors.lastname: Stein
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage*; D002135:Calcium-Binding Proteins / Q000235:genetics; D019735:Carbon-Carbon Ligases / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D000072470:Cytochrome P450 Family 4 / Q000235:genetics; D004851:Epoxide Hydrolases / Q000235:genetics; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D000071184:Pharmacogenomic Variants; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000008:administration & dosage*; D044465:White People / Q000235:genetics*
chemical_list: D000925:Anticoagulants; C510527:CALU protein, human; D002135:Calcium-Binding Proteins; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D004851:Epoxide Hydrolases; C522330:EPHX1 protein, human; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase