A Genomic Approach to Warfarin Dose Prescription in Admixed Caribbean Hispanics
Condition: Atrial Fibrillation; Deep Vein Thrombosis; Cardiac Valvular Insufficiency; Coagulopathies; Pulmonary Embolism
MeSH terms: Pulmonary Embolism; Atrial Fibrillation; Thrombosis; Embolism; Venous Thrombosis
Study type: Observational

Summary: 
      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. The
      investigators 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.
    

Detailed description: 
      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, the investigators will assess clinical validity and 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 300 patients with thromboembolic disorders receiving warfarin. Four
      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 the investigators 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.
    

Intervention name(s): Genotype-guided; Standard-of-Care
Intervention type(s): Genetic; Other
Intervention description(s): Individual warfarin dose adjustments by using a pharmacogenetically driven algorithm; Individual warfarin dose adjustments by using a clinically driven algorithm (standard care)
Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Caribbean Hispanics (e.g., Puerto Ricans, Dominicans, Cubans), whose parents are Caribbean
        Hispanics as well.
      
Biospecimen description: 
      Buccal swabs
    
Keywords: Pharmacogenomics; Warfarin; Caribbean Hispanics; Polymorphisms; Dosing Algorithm