Genome-Wide Association Study of Warfarin Maintenance Dose in a Brazilian Sample

• DOI: 10.2217/pgs.15.73
• Publication Date: 2015-08-12T10:29:07Z
• Authors: Esteban J Parra; Mariana R Botton; Jamila A Perini; S Krithika; Stephane Bourgeois; Todd A Johnson; Tatsuhiko Tsunoda; Munir Pirmohamed; Mia Wadelius; Nita A Limdi; Larisa H Cavallari; James K Burmester; Allan E Rettie; Teri E Klein; Julie A Johnson; Mara H Hutz; Guilherme Suarez-...
• Keywords: Male; 0301 basic medicine; Genotype; Anticoagulants; Middle Aged; Polymorphism, Single Nucleotide; 3. Good health; 03 medical and health sciences; Phenotype; Vitamin K Epoxide Reductases; Humans; Female; Warfarin; Brazil; Aged; Cytochrome P-450 CYP2C9; Genome-Wide Association Study

Extreme discordant phenotype and genome-wide association (GWA) approaches were combined to explore the role of genetic variants on warfarin dose requirement in Brazilians.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.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.We confirmed the important role of VKORC1 and CYP2C9 polymorphisms in warfarin dose. Original submitted 14 January 2015; Revision submitted 26 May 2015.