Journal
PHARMACOGENOMICS
Volume 16, Issue 11, Pages 1253-1263Publisher
FUTURE MEDICINE LTD
DOI: 10.2217/pgs.15.73
Keywords
1000 Genomes Project; Brazilians; CYP2C9; extreme discordant phenotypes; genome-wide association study; VKORC1; warfarin
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Funding
- Financiadora de Estudos e Projetos (Finep) [01.08.01230.00]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
- Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (Faperj)
- NIH NIGMS [R24 GM61374]
- Medical Research Council [MR/L006758/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10064] Funding Source: researchfish
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL092173] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R24GM061374] Funding Source: NIH RePORTER
- MRC [MR/L006758/1] Funding Source: UKRI
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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 (R) Biobank arrays. Imputation was carried out using data from the combined 1000 Genomes project. Results: Genome-wide signals (p <= 5 x 10(-8)) were identified in the well-known VKORC1 (lead SNP, rs749671; OR: 20.4; p = 1.08 x 10(-33)) and CYP2C9 (lead SNP, rs9332238, OR: 6.8 and p = 4.4 x 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.
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