Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Ethnicity-specific pharmacogenetics: the case of warfarin in African Americans

The Pharmacogenomics Journal volume 14, pages 223–228 (2014)Cite this article

Subjects

Abstract

Using a derivation cohort (N=349), we developed the first warfarin dosing algorithm that includes recently discovered polymorphisms in VKORC1 and CYP2C9 associated with warfarin dose requirement in African Americans (AAs). We tested our novel algorithm in an independent cohort of 129 AAs and compared the dose prediction to the International Warfarin Pharmacogenetics Consortium (IWPC) dosing algorithms. Our algorithm explains more of the phenotypic variation (R2=0.27) than the IWPC pharmacogenomics (R2=0.15) or clinical (R2=0.16) algorithms. Among high-dose patients, our algorithm predicted a higher proportion of patients within 20% of stable warfarin dose (45% vs 29% and 2% in the IWPC pharmacogenomics and clinical algorithms, respectively). In contrast to our novel algorithm, a significant inverse correlation between predicted dose and percent West African ancestry was observed for the IWPC pharmacogenomics algorithm among patients requiring ⩾60 mg per week (β=−2.04, P=0.02).

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. IMS Institute for Healthcare Informatics. The Use of Medicines in the United States, Review of 2011, Parsippany, NJ; www.theimsinstitute.org.

  2. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883–891.

    Article  CAS  PubMed  Google Scholar 

  3. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139–1151.

    Article  CAS  PubMed  Google Scholar 

  4. Harper P, Young L, Merriman E . Bleeding risk with dabigatran in the frail elderly. N Engl J Med 2012; 366: 864–866.

    Article  CAS  PubMed  Google Scholar 

  5. Cheng CM, McCurdy MR, Wong HA, Kayser SR . Pros and cons of dabigatran. Am J Health Syst Pharm 2011; 68: 1495.

    Article  PubMed  Google Scholar 

  6. Wysowski DK, Nourjah P, Swartz L . Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Int Med 2007; 167: 1414–1419.

    Article  Google Scholar 

  7. Cavallari LH, Shin J, Perera MA . Role of pharmacogenomics in the management of traditional and novel oral anticoagulants. Pharmacotherapy 2011; 31: 1192–1207.

    Article  CAS  PubMed  Google Scholar 

  8. Gage BF, Eby C, Johnson JA, Deych E, Rieder MJ, Ridker PM et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther 2008; 84: 326–331.

    Article  CAS  PubMed  Google Scholar 

  9. International Warfarin Pharmacogenetics C Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 2009; 360: 753–764.

    Article  Google Scholar 

  10. Limdi NA, Beasley TM, Crowley MR, Goldstein JA, Rieder MJ, Flockhart DA et al. VKORC1 polymorphisms, haplotypes and haplotype groups on warfarin dose among African-Americans and European-Americans. Pharmacogenomics 2008; 9: 1445–1458.

    Article  CAS  PubMed  Google Scholar 

  11. Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005; 352: 2285–2293.

    Article  CAS  PubMed  Google Scholar 

  12. Wadelius M, Chen LY, Lindh JD, Eriksson N, Ghori MJ, Bumpstead S et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood 2009; 113: 784–792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Freimuth RR, Xiao M, Marsh S, Minton M, Addleman N, Van Booven DJ et al. Polymorphism discovery in 51 chemotherapy pathway genes. Hum Mol Genet 2005; 14: 3595–3603.

    Article  CAS  PubMed  Google Scholar 

  14. Perera MA, Gamazon E, Cavallari LH, Patel SR, Poindexter S, Kittles RA et al. The missing association: sequencing-based discovery of novel SNPs in VKORC1 and CYP2C9 that affect warfarin dose in African Americans. Clin Pharmacol Ther 2011; 89: 408–415.

    Article  CAS  PubMed  Google Scholar 

  15. Perera MA, Cavallari LH, Limdi NA, Gamazon ER, Konkashbaev A, Daneshjou R et al. Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study. Lancet 2013; S0140-6736: 60681–60689.

    Google Scholar 

  16. Zakharia F, Basu A, Absher D, Assimes TL, Go AS, Hlatky MA et al. Characterizing the admixed African ancestry of African Americans. Genome Biol 2009; 10: R141.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Cavallari LH, Butler C, Langaee TY, Wardak N, Patel SR, Viana MA et al. Association of apolipoprotein E genotype with duration of time to achieve a stable warfarin dose in African-American patients. Pharmacotherapy 2011; 31: 785–792.

    Article  CAS  PubMed  Google Scholar 

  18. Hruska MW, Frye RF, Langaee TY . Pyrosequencing method for genotyping cytochrome P450 CYP2C8 and CYP2C9 enzymes. Clin Chem 2004; 50: 2392–2395.

    Article  CAS  PubMed  Google Scholar 

  19. Rosenberg NA, Li LM, Ward R, Pritchard JK . Informativeness of genetic markers for inference of ancestry. Am J Hum Genet 2003; 73: 1402–1422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Murphy AB, Ukoli F, Freeman V, Bennett F, Aiken W, Tulloch T et al. 8q24 risk alleles in West African and Caribbean men. Prostate 2012; 72: 1366–1373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wigginton JE, Cutler DJ, Abecasis GR . A note on exact tests of Hardy-Weinberg equilibrium. Am J Hum Genet 2005; 76: 887–893.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pritchard JK, Stephens M, Donnelly P . Inference of population structure using multilocus genotype data. Genetics 2000; 155: 945–959.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Cook RJ, Sackett DL . The number needed to treat: a clinically useful measure of treatment effect. BMJ 1995; 310: 452–454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cavallari LH, Langaee TY, Momary KM, Shapiro NL, Nutescu EA, Coty WA et al. Genetic and clinical predictors of warfarin dose requirements in African Americans. Clin Pharmacol Ther 2010; 87: 459–464.

    Article  CAS  PubMed  Google Scholar 

  25. Spreafico M, Lodigiani C, van Leeuwen Y, Pizzotti D, Rota LL, Rosendaal F et al. Effects of CYP2C9 and VKORC1 on INR variations and dose requirements during initial phase of anticoagulant therapy. Pharmacogenomics 2008; 9: 1237–1250.

    Article  CAS  PubMed  Google Scholar 

  26. Torres JB, Kittles RA . The relationship between "race" and genetics in biomedical research. Curr Hypertens Rep 2007; 9: 196–201.

    Article  PubMed  Google Scholar 

  27. Galanter JM, Fernandez-Lopez JC, Gignoux CR, Barnholtz-Sloan J, Fernandez-Rozadilla C, Via M et al. Development of a panel of genome-wide ancestry informative markers to study admixture throughout the Americas. PLoS Genet 2012; 8: e1002554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Parra EJ, Kittles RA, Argyropoulos G, Pfaff CL, Hiester K, Bonilla C et al. Ancestral proportions and admixture dynamics in geographically defined African Americans living in South Carolina. Am J Phys Anthropol 2001; 114: 18–29.

    Article  CAS  PubMed  Google Scholar 

  29. Parra EJ, Marcini A, Akey J, Martinson J, Batzer MA, Cooper R et al. Estimating African American admixture proportions by use of population-specific alleles. Am J Hum Genet 1998; 63: 1839–1851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kittles RA, Santos ER, Oji-Njideka NS, Bonilla C . . Race, skin color and genetic ancestry: implications for biomedical research on health disparities. Calif J Health Promotion 2007; 5 (Special Issue (Health Disparities & Social Justice): 9–23.

    Google Scholar 

  31. Goldhaber SZ . Risk factors for venous thromboembolism. J Am Coll Cardiol 2010; 56: 1–7.

    Article  PubMed  Google Scholar 

  32. Goldhaber SZ . Pulmonary embolism in Black Americans. Am J Hematol 2010; 85: 465–466.

    Article  PubMed  Google Scholar 

  33. Anderson JL, Horne BD, Stevens SM, Woller SC, Samuelson KM, Mansfield JW et al. A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). Circulation 2012; 125: 1997–2005.

    Article  CAS  PubMed  Google Scholar 

  34. Carlquist JF, McKinney JT, Nicholas ZP, Clark JL, Kahn SF, Horne BD et al. Rapid melting curve analysis for genetic variants that underlie inter-individual variability in stable warfarin dosing. J Thrombosis Thrombolysis 2008; 26: 1–7.

    Article  CAS  Google Scholar 

  35. O'Donnell PH, Bush A, Spitz J, Danahey K, Saner D, Das S et al. The 1200 patients project: creating a new medical model system for clinical implementation of pharmacogenomics. Clin Pharmacol Ther 2012; 92: 446–449.

    Article  CAS  PubMed  Google Scholar 

  36. Shin J, Cao D . Comparison of warfarin pharmacogenetic dosing algorithms in a racially diverse large cohort. Pharmacogenomics 2011; 12: 125–134.

    Article  CAS  PubMed  Google Scholar 

  37. Ramirez AH, Shi Y, Schildcrout JS, Delaney JT, Xu H, Oetjens MT et al. Predicting warfarin dosage in European-Americans and African-Americans using DNA samples linked to an electronic health record. Pharmacogenomics 2012; 13: 407–418.

    Article  CAS  PubMed  Google Scholar 

  38. Voora D, Koboldt DC, King CR, Lenzini PA, Eby CS, Porche-Sorbet R et al. A polymorphism in the VKORC1 regulator calumenin predicts higher warfarin dose requirements in African Americans. Clin Pharmacol Ther 2010; 87: 445–451.

    Article  CAS  PubMed  Google Scholar 

  39. Absher RK, Moore ME, Parker MH . Patient-specific factors predictive of warfarin dosage requirements. Ann Pharmacother 2002; 36: 1512–1517.

    Article  PubMed  Google Scholar 

  40. Hoggart CJ, Parra EJ, Shriver MD, Bonilla C, Kittles RA, Clayton DG et al. Control of confounding of genetic associations in stratified populations. Am J Hum Genet 2003; 72: 1492–1504.

    Article  CAS  PubMed  Google Scholar 

  41. Kittles RA, Race Weiss KM . ancestry, and genes: implications for defining disease risk. Ann Rev Genomics Hum Genet 2003; 4: 33–67.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was funded in part by the National Heart Lung and Blood Institute (K23 HL089808-01A2 to MAP), a grant from the American Heart Association Midwest Affiliate Grant-In-Aid (10GRNT3750024 to LHC) and by a grant from the National Collaborative on Aging (TJO).

Author information

Authors and Affiliations

  1. Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, IL, USA

    W Hernandez, E R Gamazon, K Aquino-Michaels, D Nicolae & M A Perera

  2. Department of Pharmacy, University of Illinois, Chicago, IL, USA

    S Patel & L H Cavallari

  3. Department of Pharmacology and Physiology, The George Washington University, Washington, DC, USA

    T J O'Brien & A F Harralson

  4. Department of Pharmacogenomics, Bernard J. Dunn School of Pharmacy, Shenandoah University, Ashburn, VA, USA

    A F Harralson

  5. Department of Medicine, Institute of Human Genetics, University of Illinois, Chicago, IL, USA

    R A Kittles

  6. Department of Medicine, The George Washington University, Washington, DC, USA

    A Barbour & S D McIntosh

  7. Department of Veterans Affairs, Uniformed Services University of the Health Sciences, Washington, DC, USA

    M Tuck, S D McIntosh & J N Douglas

Authors
  1. W Hernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E R Gamazon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Aquino-Michaels
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T J O'Brien
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A F Harralson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R A Kittles
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Barbour
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Tuck
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S D McIntosh
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. J N Douglas
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. D Nicolae
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. L H Cavallari
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. M A Perera
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M A Perera.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hernandez, W., Gamazon, E., Aquino-Michaels, K. et al. Ethnicity-specific pharmacogenetics: the case of warfarin in African Americans. Pharmacogenomics J 14, 223–228 (2014). https://doi.org/10.1038/tpj.2013.34

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2013.34

Keywords

This article is cited by

Search

Advanced search

Quick links