title: VKORC1 V66M mutation in African Brazilian patients resistant to oral anticoagulant therapy.
abstract: Warfarin-based anticoagulant therapy is associated with large variability in dose response. Genetic variability in the VKORC1 and CYP2C9 genes is associated with increased warfarin sensitivity. In addition, rare coding region mutations in VKORC1 have been associated with resistance to warfarin. VKORC1 and CYP2C9 variability associated with altered warfarin response is less well characterized in African and mixed-raced populations such as Brazilians. To determine genetic variability associated with altered warfarin response among Brazilian patients, sixty-two adult patients with extreme resistance or sensitivity to warfarin were genotyped for variants in CYP2C9 and VKORC1. Of the 51 patients on low doses of warfarin, the VKORC1--1639 (3673) G>A polymorphism associated with warfarin sensitivity was present in 48 (94.1%), including 97% of Caucasians, 82% of African-descent patients, and all 7 (100%) patients of Indian descent. Additionally, 52.9% of warfarin sensitive patients had at least one CYP2C9*2 or CYP2C9*3 decreased metabolism allele, 63.6% of Caucasians and 54% of African-descent patients. Of the 11 patients on high doses of warfarin, sequencing of VKORC1 revealed a nonsynonymous V66M mutation in two warfarin resistant patients, both of African-descent. Brazilian patients requiring low doses of warfarin have a high frequency of VKORC1 and CYP2C9 variants associated with warfarin sensitivity. The presence of the rare VKORC1 V66M in two warfarin high dose outlier patients implies that this variant may be more frequent among African Brazilians and has implications for future warfarin studies in other populations of African descent.
authors.affiliation: Hematology and Hemotherapy Center, State University of Campinas, Brazil. ferorsi@unicamp.br
authors.forename: Fernanda A
authors.initials: FA
authors.lastname: Orsi
authors.forename: Joyce M
authors.initials: JM
authors.lastname: Annichino Bizzacchi
authors.forename: Erich V
authors.initials: EV
authors.lastname: de Paula
authors.forename: Margareth C
authors.initials: MC
authors.lastname: Ozelo
authors.forename: Michael R
authors.initials: MR
authors.lastname: Langley
authors.forename: Karen E
authors.initials: KE
authors.lastname: Weck
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D044383:Black People / Q000235:genetics*; D001777:Blood Coagulation / Q000187:drug effects* / Q000235:genetics; D001938:Brazil; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage*; D055815:Young Adult
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