Despite the substantial number of work published over the past years in different populations around the world, a fundamental gap remains in understanding whether and how genomic admixture and polymorphisms in warfarin-related pharmacogenes account for the high inter-individual dose variability observed in Caribbean Hispanic patients. In addition to being a medically underserved population, often marginally represented in clinical studies, Caribbean Hispanics are also a genomically heterogeneous population whose high level of admixture has produced a rich repertoire of combinatorial genotypes (e.g., CYP2C9*2/*5 + VKORC1-1639 A/A) that appear to challenge current pharmacogenetic-driven prescribing models. Our project takes a novel approach to definitively assess this admixture component and is also highly practical for its incorporation into a customized pharmacogenetic algorithm that will be implemented in """"""""real-world"""""""" clinical settings through a web- based portal. Moreover, the project is also aimed at performing DNA-sequencing to identify those unknown variants on candidate pharmacogenes (i.e., CYP2C9 and VKORC1) that may contribute further to explain dose variability in Caribbean Hispanics. Shaped by strong preliminary data from a SC2 pilot project, we will: Derive and further assess validity and clinical utility of an admixture-adjusted, pharmacogenetic-guided prescribing model for personalized prediction of effective warfarin dosing in Caribbean Hispanics, which also encompasses genetic (common and novel variants) and non-genetic clinical and demographic factors. The study will be conducted over 4 years in 850 patients with thromboembolic disorders receiving warfarin. Two collaborating recruiting sites will be further connected through precise delivery of genotyping results and prescribing advice to clinicians via a web-based portal. Our novel assessment of genetic admixture will quantify the contribution of European, African and Amerindian ancestry, and we will test whether this admixture component can explain the heritability that is currently missing in the response variability to this drug among Caribbean Hispanics. If successful in our target population, the same approach can ultimately render current pharmacogenomic models for clinical management of related thromboembolic conditions more accurate and predictive for other populations. The proposed research will advance and expand our understanding of how these clinically relevant variants affect the response to warfarin in an admixed population. Advancing knowledge in the important and under- investigated area of pharmacogenetics in minority populations will generate results that apply to personalize oral anticoagulation therapy in the wider population as it moves, inevitably, toward increasing heterogeneity through admixed genomes. The ultimate goal is to gather strong data in support of a R01-equivalent application.

Public Health Relevance

Caribbean Hispanics are a population with a disproportionately high prevalence of cardio-metabolic disorders but with a limited expectation of benefits from current pharmacogenetic algorithms derived mainly in subjects of relatively pure ancestry. We focus on warfarin responses to develop urgently-needed DNA-driven prescription guidelines for this population, who have arisen from European, West African and Amerindian genomic origins to produce a highly heterogeneous population. Our project combines admixture analysis and DNA-sequencing with development of more accurate rules for better predictability of warfarin dosing to immediately serve this medically underserved population.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Enhancement Award (SC1)
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Special Emphasis Panel (ZGM1)
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Kindzelski, Andrei L
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University of Puerto Rico Med Sciences
San Juan
United States
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Hernandez-Suarez, Dagmar F; Botton, Mariana R; Scott, Stuart A et al. (2018) Pharmacogenetic association study on clopidogrel response in Puerto Rican Hispanics with cardiovascular disease: a novel characterization of a Caribbean population. Pharmgenomics Pers Med 11:95-106
Hernandez-Suarez, Dagmar F; Núñez-Medina, Hector; Scott, Stuart A et al. (2018) Effect of cilostazol on platelet reactivity among patients with peripheral artery disease on clopidogrel therapy. Drug Metab Pers Ther 33:49-55
Martes-Martinez, Carlos; Méndez-Sepúlveda, Cristian; Millán-Molina, Joel et al. (2017) Cost-Utility Study of Warfarin Genotyping in the VACHS Affiliated Anticoagulation Clinic of Puerto Rico. P R Health Sci J 36:165-172
Claudio-Campos, Karla; Labastida, Aurora; Ramos, Alga et al. (2017) Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study. Front Pharmacol 8:347
Duconge, Jorge; Hernandez-Suarez, Dagmar F (2017) Potential Usefulness of Clopidogrel Pharmacogenetics in Cerebral Endovascular Procedures and Carotid Artery Stenting. Curr Clin Pharmacol 12:11-17
Hernandez-Suarez, Dagmar F; Scott, Stuart A; Tomey, Matthew I et al. (2017) Clinical determinants of clopidogrel responsiveness in a heterogeneous cohort of Puerto Rican Hispanics. Ther Adv Cardiovasc Dis 11:235-241
Duconge, Jorge; Ruaño, Gualberto (2016) Admixture and ethno-specific alleles: missing links for global pharmacogenomics. Pharmacogenomics 17:1479-82
Hernandez-Suarez, Dagmar F; Claudio-Campos, Karla; Mirabal-Arroyo, Javier E et al. (2016) Potential of a Pharmacogenetic-Guided Algorithm to Predict Optimal Warfarin Dosing in a High-Risk Hispanic Patient: Role of a Novel NQO1*2 Polymorphism. J Investig Med High Impact Case Rep 4:2324709616682049
Céspedes-Garro, Carolina; Naranjo, María-Eugenia G; Rodrigues-Soares, Fernanda et al. (2016) Pharmacogenetic research activity in Central America and the Caribbean: a systematic review. Pharmacogenomics 17:1707-1724
Duconge, Jorge; Ramos, Alga S; Claudio-Campos, Karla et al. (2016) A Novel Admixture-Based Pharmacogenetic Approach to Refine Warfarin Dosing in Caribbean Hispanics. PLoS One 11:e0145480

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