VKORC1 polymorphims, haplotypes and haplotype groups on warfarin dose among African-Americans and European-Americans

Nita A. Limdi, T. Mark Beasley, Michael R. Crowley, Joyce A. Goldstein, Mark J. Rieder, David A. Flockhart, Donna K. Arnett, Ronald T. Acton, Nianjun Liu

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

Background: Although the influence of VKORC1 and CYP2C9 polymorphisms on warfarin response has been studied, variability in dose explained by CYP2C9 and VKORC1 is lower among African-Americans compared with European-Americans. This has lead investigators to hypothesize that assessment of VKORC1 haplotypes may help capture a greater proportion of the variability in dose for this under-represented group. However, the inadequate representation of African-Americans and the assessment of a few VKORC1 polymorphisms have hindered this effort. Methods: To determine if VKORC1 haplotypes or haplotype groups explain a higher variability in warfarin dose, we comprehensively assessed VKORC1 polymorphisms in 273 African-Americans and 302 European-Americans. The influence of VKORC1 polymorphisms, race-specific haplotypes and haplotype groups on warfarin dose was evaluated in race-stratified multivariable analyses after accounting for CYP2C9 (*2, *3, *5, *6 and *11) and clinical covariates. Results: VKORC1 explained 18% (30% with CYP2C9) variability in warfarin dose among European-Americans and 5% (8% with CYP2C9) among African-Americans. Four common haplotypes in European-Americans and twelve in African-Americans were identified. In each race VKORC1 haplotypes emerged into two groups: low-dose (Group A) and high-dose (Group B). African-Americans had a lower frequency of Group A haplotype (10.6%) compared with European-Americans (35%, p < 0.0001). The variability in dose explained by VKORC1 haplotype or haplotype groups was similar to that of a single informative polymorphism. Conclusions: Our findings support the use of CYP2C9, VKORC1 polymorphisms (rs9934438 or rs9923231) and clinical covariates to predict warfarin dose in both African- and European-Americans, A uniform set of common polymorphisms in CYP2C9 and VKORC1, and limited clinical covariates can be used to improve warfarin dose prediction for a racially diverse population.

Original languageEnglish (US)
Pages (from-to)1445-1458
Number of pages14
JournalPharmacogenomics
Volume9
Issue number10
DOIs
StatePublished - Nov 11 2008

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Keywords

  • African-Americans
  • Cohort study
  • CYP2C9
  • European-Americans
  • Haplotypes
  • Pharmacogenetics
  • VKORC1
  • Warfarin

ASJC Scopus subject areas

  • Pharmacology
  • Genetics
  • Molecular Medicine

Cite this

Limdi, N. A., Beasley, T. M., Crowley, M. R., Goldstein, J. A., Rieder, M. J., Flockhart, D. A., Arnett, D. K., Acton, R. T., & Liu, N. (2008). VKORC1 polymorphims, haplotypes and haplotype groups on warfarin dose among African-Americans and European-Americans. Pharmacogenomics, 9(10), 1445-1458. https://doi.org/10.2217/14622416.9.10.1445