Warfarin is a frequently prescribed drug for both the treatment and prevention of thromboembolic complications. Although many reports have been published over the past years in different populations worldwide, there is a fundamental gap in understanding whether variations in CYP2C9 and VKORC1 genes account for the inter-individual variability in response to warfarin that is observed in Puerto Rican patients. This study is a first step toward the development of DNA-driven personalized guidelines for warfarin dose optimization in Puerto Rican patients with thromboembolic complications. Guided by strong preliminary data, this application will pursuit two specific aims: 1) Develop a physiogenomic (PG)-driven admixture analysis of 350 samples from a population of warfarin-treated Puerto Rican patients using the PG array in order to study the pharmacogenetics of warfarin in Puerto Ricans and 2) Determine whether combinatorial CYP2C9 and VKORC1 genotypes are associated with clinical phenotypes during warfarin therapy in Puerto Rican patients. Under the first aim, 350 DNA specimens from warfarin-treated Puerto Rican patients who consent to participate in this study will be genotyped at large-scale using a novel Illumina-based PG-array of 222 candidate genes from relevant cardio-metabolic and neuro-endocrine pathways in order to examine the population structure of Puerto Ricans and create a reference database of individual admixture, allele frequencies, linkage disequilibrium (LD) and haplotypes for pharmacogenetics studies. Noteworthy, this information remains to be determined in Puerto Ricans. Under the second aim, demographic and clinically relevant non-genetic data will be retrospectively collected from medical records of these patients in order to perform an association analysis between their previously obtained CYP2C9 and VKORC1 genotypes and the corresponding time to achieve stable warfarin dosing following survival analysis techniques and Cox proportional hazards model. Accomplishment of this specific aim will also give the basis for developing a DNA-guided warfarin dosing algorithm in Puerto Rican by using these patients as a learning sample. The long-term goal is to generate valuable information from the genetic background of Puerto Ricans in order to further validate the pharmacogenetic-driven warfarin dosing algorithm for this admixed population. The proposed research is significant because it is expected to advance and expand understanding of how these clinically relevant variants affect the way people from an admixed, under-served population respond to warfarin. This is an important and under-investigated area of pharmacogenetics in minority populations that will have potential applicability to personalize warfarin therapy.

Public Health Relevance

The Support of Competitive Research Program SC2 mechanism is intended to encourage pilot and developmental research projects by providing support for increasing competitiveness of faculty members at minority-serving institutions who are in their early stages of development and are seeking to gather preliminary data. The proposed studies will fill a gap in the pharmacogenetics of warfarin, providing new information on the prevalence of CYP2C9 (metabolism) and VKORC1 (sensitivity) polymorphisms in Puerto Ricans as well as their role in the warfarin response variability observed in this admixed population. I am a new investigator and faculty member at the University of Puerto Rico Medical Sciences Campus, a minority-serving institution, and this SC2-type pilot project is my first attempt to obtain external federal funds. This mechanism will support my initial career development as a pharmacogeneticist interested in better understanding the genetic basis of the observed drug response variability among Puerto Ricans, by conducting a pilot pharmacogenetic study in this under-served population that might address potential health disparities in the clinical management of warfarin therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Pilot Research Project (SC2)
Project #
5SC2HL110393-03
Application #
8423733
Study Section
Special Emphasis Panel (ZGM1-MBRS-X (GC))
Program Officer
Link, Rebecca P
Project Start
2011-02-07
Project End
2014-07-31
Budget Start
2013-02-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$107,100
Indirect Cost
$35,700
Name
University of Puerto Rico Med Sciences
Department
Pharmacology
Type
Schools of Medicine
DUNS #
948108063
City
San Juan
State
PR
Country
United States
Zip Code
00936
Valentín, Isa I; Rivera, Giselle; Nieves-Plaza, Mariely et al. (2014) Pharmacogenetic association study of warfarin safety endpoints in Puerto Ricans. P R Health Sci J 33:97-104
Valentin, Isa Ivette; Vazquez, Joan; Rivera-Miranda, Giselle et al. (2012) Prediction of warfarin dose reductions in Puerto Rican patients, based on combinatorial CYP2C9 and VKORC1 genotypes. Ann Pharmacother 46:208-18