Genome-wide association study of warfarin maintenance dose in a Brazilian sample.
OBJECTIVE
Extreme discordant phenotype and genome-wide association (GWA) approaches were combined to explore the role of genetic variants on warfarin dose requirement in Brazilians.


METHODS
Patients receiving low (≤ 20 mg/week; n = 180) or high stable warfarin doses (≥ 42.5 mg/week; n = 187) were genotyped with Affymetrix Axiom(®) Biobank arrays. Imputation was carried out using data from the combined 1000 Genomes project.


RESULTS
Genome-wide signals (p ≤ 5 × 10(-8)) were identified in the well-known VKORC1 (lead SNP, rs749671; OR: 20.4; p = 1.08 × 10(-33)) and CYP2C9 (lead SNP, rs9332238, OR: 6.8 and p = 4.4 × 10(-13)) regions. The rs9332238 polymorphism is in virtually perfect LD with CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910). No other genome-wide significant regions were identified in the study.


CONCLUSIONS
We confirmed the important role of VKORC1 and CYP2C9 polymorphisms in warfarin dose. Original submitted 14 January 2015; Revision submitted 26 May 2015.
Department of Anthropology, University of Toronto at Mississauga, ON, Canada.
Esteban J
EJ
Parra
Department of Genetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Mariana R
MR
Botton
Pharmacology Division, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
Jamila A
JA
Perini
Department of Anthropology, University of Toronto at Mississauga, ON, Canada.
S
S
Krithika
William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, UK.
Stephane
S
Bourgeois
Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Japan.
Todd A
TA
Johnson
Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Japan.
Tatsuhiko
T
Tsunoda
Department of Molecular & Clinical Pharmacology, University of Liverpool, UK.
Munir
M
Pirmohamed
Department of Medical Sciences, Clinical Pharmacology & Science for Life Laboratory, Uppsala University, Sweden.
Mia
M
Wadelius
Department of Neurology, University of Alabama at Birmingham, AL, USA.
Nita A
NA
Limdi
University of Florida, Department of Pharmacotherapy & Translational Research, FL, USA.
Larisa H
LH
Cavallari
Clinical Research Center, Marshfield Clinic Research Foundation, WI, USA.
James K
JK
Burmester
Department Medicinal Chemistry, School of Pharmacy, University of Washington, WA, USA.
Allan E
AE
Rettie
Department of Genetics, Stanford University School of Medicine, CA, USA.
Teri E
TE
Klein
University of Florida, Department of Pharmacotherapy & Translational Research, FL, USA.
Julie A
JA
Johnson
Department of Genetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Mara H
MH
Hutz
Pharmacology Division, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
Guilherme
G
Suarez-Kurtz
D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage* / Q000627:therapeutic use*; D001938:Brazil / Q000453:epidemiology; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000008:administration & dosage* / Q000627:therapeutic use*
D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases
1000 Genomes Project; Brazilians; CYP2C9; VKORC1; extreme discordant phenotypes; genome-wide association study; warfarin