Development of a Pharmacogenetic-Guided Warfarin Dosing Algorithm for Puerto Rican Patients

Abstract

Aim: This study was aimed at developing a pharmacogenetic-driven warfarin-dosing algorithm in 163 admixed Puerto Rican patients on stable warfarin therapy. Patients & methods: A multiple linear-regression analysis was performed using log-transformed effective warfarin dose as the dependent variable, and combining CYP2C9 and VKORC1 genotyping with other relevant nongenetic clinical and demographic factors as independent predictors. Results: The model explained more than two-thirds of the observed variance in the warfarin dose among Puerto Ricans, and also produced significantly better ‘ideal dose‘ estimates than two pharmacogenetic models and clinical algorithms published previously, with the greatest benefit seen in patients ultimately requiring <7 mg/day. We also assessed the clinical validity of the model using an independent validation cohort of 55 Puerto Rican patients from Hartford, CT, USA (R² = 51%). Conclusion: Our findings provide the basis for planning prospective pharmacogenetic studies to demonstrate the clinical utility of genotyping warfarin-treated Puerto Rican patients.

Original submitted 2 August 2012; Revision submitted 2 October 2012

KEYWORDS::

• algorithm
• CYP2C9
• genotyping
• personalized medicine
• pharmacogenetics
• VKORC1
• warfarin

Acknowledgements

The authors thank the RCMI Center for Genomics in Health Disparities and Rare Disorders for their facilities for blood and DNA specimens‘ storage. The authors also want to thank L Montaner for his critical review of this work, and C Perez, H-L Venegas-Rios, M Nieves, J Vazquez, I-I Valentin and A Amaro for their help in this survey.

Financial & competing interests disclosure

This investigation was funded in part by the grant #SC2HL110393 from the National Heart, Lung and Blood Institute (NHLBI, NIH); the Research Center in Minority Institutions (RCMI) grants from the National Center for Research Resources (award# 2G12-RR003051) and the National Institute on Minority Health and Health Disparities, NIH (award# 8G12-MD007600); and Hartford Hospital Grant #123260. The authors also thank support from the Biostatistical Core of the Puerto Rico Clinical & Translational Research Consortium through grant #8U54MD007587 (NIMHD-NIH). G Ruaño is founder and President of Genomas Inc., and M Kocherla and K Gorowski are full-time employees of Genomas. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that appropriate institutional review board (IRB) approvals from the Veteran Affair Caribbean Healthcare System (VACHS), Hartford Hospital and UPR-MSC were granted and the principles outlined in the Declaration of Helsinki for human experimental procedures were followed at any time. In addition, written informed consents have been obtained from all the participants involved in this survey.

Additional information

Funding

This investigation was funded in part by the grant #SC2HL110393 from the National Heart, Lung and Blood Institute (NHLBI, NIH); the Research Center in Minority Institutions (RCMI) grants from the National Center for Research Resources (award# 2G12-RR003051) and the National Institute on Minority Health and Health Disparities, NIH (award# 8G12-MD007600); and Hartford Hospital Grant #123260. The authors also thank support from the Biostatistical Core of the Puerto Rico Clinical & Translational Research Consortium through grant #8U54MD007587 (NIMHD-NIH). G Ruaño is founder and President of Genomas Inc., and M Kocherla and K Gorowski are full-time employees of Genomas. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.