title: Copy number variation and warfarin dosing: evaluation of CYP2C9, VKORC1, CYP4F2, GGCX and CALU.
abstract: OBJECTIVE
  To determine if copy number variants contribute to warfarin dose requirements, we investigated CYP2C9, VKORC1, CYP4F2, GGCX and CALU for deletions and duplications in a multiethnic patient population treated with therapeutic doses of warfarin.
  
  
  METHODS
  DNA samples from 178 patients were subjected to copy number analyses by multiplex ligation-dependent probe amplification or quantitative PCR assays. Additionally, the CYP2C9 exon 8 insertion/deletion polymorphism (rs71668942) was examined among the patient cohort and 1750 additional multiethnic healthy individuals.
  
  
  RESULTS
  All patients carried two copies of CYP2C9 by multiplex ligation-dependent probe amplification and no exon 8 deletion carriers were detected. Similarly, quantitative PCR assays for VKORC1, CYP4F2, GGCX and CALU identified two copies in all populations.
  
  
  CONCLUSIONS
  These data indicate that copy number variants in the principal genes involved in warfarin dose variability (CYP2C9, VKORC1), including genes with lesser effect (CYP4F2, GGCX), and those that may be more relevant among certain racial groups (CALU), are rare in multiethnic populations, including African-Americans.
authors.affiliation: Department of Genetics & Genomic Sciences, Box 1497, Mount Sinai School of Medicine, 1428 Madison Avenue, New York, NY 10029, USA. stuart.scott@mssm.edu
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Scott
authors.forename: Manishkumar
authors.initials: M
authors.lastname: Patel
authors.forename: Suparna
authors.initials: S
authors.lastname: Martis
authors.forename: Steven A
authors.initials: SA
authors.lastname: Lubitz
authors.forename: Sarina
authors.initials: S
authors.lastname: van der Zee
authors.forename: Chang
authors.initials: C
authors.lastname: Yoo
authors.forename: Lisa
authors.initials: L
authors.lastname: Edelmann
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Halperin
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D019735:Carbon-Carbon Ligases / Q000235:genetics*; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D056915:DNA Copy Number Variations / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005006:Ethnicity / Q000235:genetics; D005091:Exons; D005260:Female; D017353:Gene Deletion; D020440:Gene Duplication; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; C510527:CALU protein, human; D002135:Calcium-Binding Proteins; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase