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. 2015;16(11):1253-63.
doi: 10.2217/PGS.15.73. Epub 2015 Aug 12.

Genome-wide association study of warfarin maintenance dose in a Brazilian sample

Esteban J Parra  1 , Mariana R Botton  2 , Jamila A Perini  3 , S Krithika  1 , Stephane Bourgeois  4 , Todd A Johnson  5 , Tatsuhiko Tsunoda  5 , Munir Pirmohamed  6 , Mia Wadelius  7 , Nita A Limdi  8 , Larisa H Cavallari  9 , James K Burmester  10 , Allan E Rettie  11 , Teri E Klein  12 , Julie A Johnson  9 , Mara H Hutz  2 , Guilherme Suarez-Kurtz  3
Affiliations

Genome-wide association study of warfarin maintenance dose in a Brazilian sample

Esteban J Parra et al. Pharmacogenomics. 2015.

Abstract

Aim: 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.

Conclusion: We confirmed the important role of VKORC1 and CYP2C9 polymorphisms in warfarin dose. Original submitted 14 January 2015; Revision submitted 26 May 2015.

Keywords: 1000 Genomes Project; Brazilians; CYP2C9; VKORC1; extreme discordant phenotypes; genome-wide association study; warfarin.

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Figures

Figure 1
Figure 1. Histogram showing the frequency distribution of weekly warfarin dose in the Brazilian sample
Patients at opposite ends of the distribution (gray bars) were selected for genotyping with the Affymetrix Axiom® Biobank
Figure 2
Figure 2
Regional plot of the VKORC1 region.
Figure 3
Figure 3
Regional plot of the CYP2C9 region.
See this image and copyright information in PMC

References

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