Pharmacogenetics of Warfarin in Puerto Ricans.
Condition: Atrial Fibrillation; Deep Vein Thrombosis; Cardiac Valvular Insufficiency; Antiphospholipid Syndrome; Coagulopathy
MeSH terms: Atrial Fibrillation; Thrombosis; Venous Thrombosis; Antiphospholipid Syndrome
Study type: Observational

Summary: 
      Warfarin (Coumadin) is a prescribed "blood thinner" medication used to make the blood less
      thick in people with high risk of forming blood clots. Despite the various methods to monitor
      this drug, life-threatening bleeding is a common undesired effect and might result in patient
      death. Patients starting warfarin therapy may require several weeks or even months to reach
      the appropriate blood level of warfarin. This blind practice could place the patient at high
      risk. There are several demographic and clinical factors that significantly influence how
      much warfarin the patient needs to attain the desired response. Genes, which control
      hereditary traits, are also important. Now, the investigators know that by using the
      information encoded in patient's genes the investigators are able to individualize the
      therapy. Two genes are considered to be involved in warfarin response (CYP2C9 and VKORC1).
      This study proposes to ascertain what CYP2C9 and VKORC1 variants are present in
      warfarin-treated Puerto Rican patients. To this purpose, a novel physiogenomic array
      comprising 384 variants in 222 genes of cardio-metabolic relevance will be used so the
      investigators are able to determine the structure of the Puerto Rican population in terms of
      ancestral contributions and how the admixture may impact the prevalence of CYP2C9 and VKORC1
      variants. Secondly, the investigators will assess the association of these variants to
      clinical responses in order to develop a better method of dose estimation. The expected
      result is the improvement of warfarin therapy in Puerto Ricans. The proposed study will fill
      a gap in the knowledge of warfarin pharmacogenetics, 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.
    

Detailed description: 
      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.
    

Observational model: Cohort
Time perspective: Retrospective
Sampling method: Non-Probability Sample
Study population: 
        Hispanic Puerto Rican patients from all geographic regions of the Island of Puerto Rico who
        are currently receiving a standard stable dose of warfarin at the anticoagulation clinic of
        the Veteran Affair Caribbean Healthcare System (VACHS)
      
Biospecimen description: 
      Whole fresh blood and Genomic DNA samples fom enrolled patients
    
Keywords: Pharmacogenetics; Warfarin; Personalized Medicine; Puerto Ricans; Physiogenomics; Hispanics; Anticoagulants; Cardiovascular; Deep Vein Thrombosis with or without Pulmonary Embolism; Cardiac Valvular Replacement