Project description:Warfarin is an oral anticoagulant and one of the most used drugs in the world accounting for up to 1.5% of prescriptions globally. Warfarin inhibits vitamin K epoxide reductase complex 1 (VKORC1), an enzyme responsible for the vitamin K recycling that is required for the activation of clotting factors. Warfarin is prescribed at an average dose of 5 mg/day for most of the indications but significant inter-patient variability has been observed. Single nucleotide variations at the VKORC1 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=VKORC1">GeneID: 79001</a>) and CYP2C9 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=CYP2C9">GeneID: 1559</a>) genes alone explain from 28 to 35% of variability in warfarin dose requirements and up to 56% when clinical factors (age, gender, body surface area, diabetes and heart valve) are incorporated into regression analysis. However, genetic-guided dosing algorithms are mostly derived from studies in Europeans. The objective of the present study was to identify genetic polymorphisms that can explain variability in warfarin dose requirements among Caribbean Hispanics of Puerto Rico. VKORC1 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=VKORC1">GeneID: 79001</a>) and CYP2C9 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=CYP2C9">GeneID: 1559</a>), the most important genetic predictors of warfarin response, were sequenced using Next Generation sequencing. Other candidate genes in DMET Plus Assay were assessed to identify genetic variants with relevance in warfarin dose requirements among Puerto Ricans. Our study used the Extreme Discordant Phenotype approach to perform a case-control association analysis that were confirmed with univariate and conditioned regressions. Accordingly, patients were stratified based on stable warfarin doses as sensitive (<4 mg/day), control (4-6 mg/day) and resistant (>6 mg/day). Genetic variants associated with warfarin response among the study cohort were used to perform a multivariate regression analyses to develop a genetic-guided dosing algorithm tailored for Puerto Ricans. The CYP2C9rs2860905 SNP was found to be strongly associated with warfarin dose requirements in Puerto Ricans. The CYP2C9 rs2860905 SNP tags four haplotypes that represent the trihybrid admixture of Puerto Ricans. Therefore, haplotypes harboring the rs2860905 variant are more informative in predicting warfarin dose among Puerto Ricans than the common single segregating SNPs (i.e., CYP2C9*2 and CYP2C9*3) relevant to Europeans. DMET Plus array confirmed the strong association of VKORC1 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=VKORC1">GeneID: 79001</a>) and CYP2C9 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=CYP2C9">GeneID: 1559</a>) with warfarin dose requirements, but also identified other polymorphisms in CES2 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=CES2">GeneID: 8824</a>) and ABCB1 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=ABCB1">GeneID: 5243</a>) associated with warfarin resistance (>6 mg/day). Ancestry analysis showed that Puerto Ricans from Veteran Affairs Caribbean Healthcare System (VACHS) using warfarin had higher Native American proportions than Puerto Ricans from the 1000 Genomes project; however, this difference was not significant. Incorporation of rs2860905 in a regression model (R2=0.60 MSE=0.38) that also included additional genetic predictors (i.e., VKORC1-1639G>A; CYP2C9 rs1856908; ABCB1 rs10276036; CES2 rs4783745) and non-genetic factors (i.e., hypertension, diabetes and age) showed better prediction of warfarin dose requirements than CYP2C9*2 and CYP2C9*3 combined (partial R2=0.132 versus 0.023 and 0.007, respectively, p<0.001). Interestingly, deep vein thrombosis and diabetes were found associated with high warfarin dose requirements among Puerto Ricans. Our results support the use of CYP2C9 rs2860905 along with other genetic markers [e.g., VKORC1(<a href="https://www.ncbi.nlm.nih.gov/gene/?term=VKORC1">GeneID: 79001 </a>)] and clinical covariates to predict warfarin dose in Puerto Ricans. Although our findings need further replication, this study contributes to the field of Pharmacogenetics and to improve anticoagulation therapy among Puerto Ricans.

Project description:The GOAL Study was designed to comprehensively evaluate the genomic architecture of diverse Hispanic/Latino individuals with origins from the Caribbean, Central and South America, and to understand the impact of this diversity on genetic disease studies. Population structure and admixture are key confounders in genome-wide association and medical resequencing studies. In particular, accounting for difference in ancestry among cases and controls, both in terms of genomic and geographic location, is critical for proper analysis and interpretation of studies with multi- and trans-ethnic samples. Genomic studies of Hispanics/Latinos, the largest and fastest growing minority group in the US, reveal that they are a highly genetically heterogeneous admixed group with immense variation among individuals and populations in the proportions of African, European, and Native American ancestry. Knowledge of the underlying complex genetic structure of US Hispanic/Latino and Caribbean populations is, therefore, essential to ensuring robustness of genotype-phenotype associations and understanding the medical relevance of associated variants across diverse populations in the US and throughout the Americas. Furthermore, since much is known about the African and European migrations into the Americas over the past 500 years, population genetic studies of Hispanics/Latinos serve as an excellent model for developing novel algorithms and approaches for characterizing fine-scale genetic structure of admixed populations, in general. This project extends current studies of population genetic structure in US Hispanics/Latinos by densely genotyping parent-offspring triads from individuals (sampled in the US) of Caribbean-descent from six Latin American countries: Puerto Rico, Cuba, Dominican Republic, Haiti, Honduras and Colombia. This study will provide immediate insights and new statistical methods to improve study design and genetic analysis for medical genomic studies in Hispanics/Latinos, other complex admixed groups, and multi- and trans-ethnic studies.

Project description:Although the efficacy of warfarin in the treatment and prevention of thromboembolic disorders is proven, it is vastly underutilized with difficulties in management and risk of complications being the main deterrents. Recognition of genetic regulation of warfarin response has fueled efforts to quantify this influence, but the focus has been restricted to select genes and outcomes mainly in European Americans. Race appears to influence warfarin dose requirements with African Americans requiring larger and Asians requiring lower doses compared to Europeans. This variation in dose requirement by race may at least partially be explained by genetic differences. The Genetic and Environmental Determinants of Warfarin Response (GEDWR) and the Pharmacogenetic Optimization of Anticoagulation Therapy (POAT) are prospective cohort study aimed at defining the influence of CYP2C9, VKORC1 and other genes. All patients were followed at monthly intervals from initiation of therapy. At each visit factors influencing warfarin response such as warfarin dose, INR, concurrent medications, etc. were documented. Information on concurrent medications was updated at every clinic visit by self-report and verified by medical record review. Concomitant use of drugs such as drugs that alter warfarin pharmacokinetics, including CYP2C9 inhibitors (e.g., amiodarone), and pharmacodynamics such as antiplatelet agents (e.g. aspirin). Although the a priori hypothesis focused on the candidate-gene approach, with the recognition that the candidate-gene approach is bound by the assumption that our knowledge of genetic influences on warfarin response is complete. Among African Americans known variation in candidate genes (CYP2C9 and VKORC1) explain substantially less variability in warfarin dose requirements. Therefore a genome-wide association study (GWAS) was conducted on African American patients to identify novel variants associated with warfarin dose requirements.

Project description:Integrated Approaches to Testing and Assessment (IATA) are emerging as a means to strategically assess and test chemicals for toxicity, using existing information, and helping to identify potential data gaps. Adverse Outcome Pathways (AOPs) have recently been shown to be a good starting point for IATA development. Our interest in IATAs and AOP Networks (AOPNs) focuses on developing efficient testing and risk assessment strategies for new materials, new chemical entities, and setting environmental cleanup goals. We combine the maths logic of causality, specifically the notion of sufficiency to infer an adverse outcome, with AOPNs to develop Minimally Sufficient Sets of Key Events (MinSSKEs). These MinSSKEs represent a set of key events (can just be one key event) that taken together allow assessors to predict if an adverse outcome is likely or not. For our case study we use the military explosive trinitrotoluene (TNT). TNT is a relatively data rich chemical where the US Environmental Protection Agency has set a reference dose of 0.0005mg/kg-day, based on a point of departure for liver toxicity in dogs of 0.5mg/kg-day (a lowest observed adverse effect level; LOAEL) with uncertainty of 1,000X. Our IATA measures gene expression for genes in involved in our AOPN for energy metabolism, steatosis and oxidative stress in human induced pluripotent stem cells differentiated to hepatocytes exposed to TNT. We used a Bayesian statistical approach to identify differentially expressed genes, and a nonlinear data-driven dose-response modeling approach (Good Risk Assessment Values for Environmental Exposures; GRAVEE) to estimate points of departure for reference dose estimation. We obtained an RfD of 0.12mg/kg-day, with a 90% credible interval spanning from 0.02-0.19mg/kg-day using our IATA approach. Our RfD is based on a POD of 1.22mg/kg-day with a 90% credible interval spanning from 0.24-1.94mg/kg-day, and uncertainty of 10X after applying the IRIS uncertainty factors. Our PODs are highly comparable, with a difference of only 0.72mg/kg-day (or 2.44x). Our RfDs differ by 240x, owing to the fact that we have only a 10x uncertainty factor for human variability, whereas the IRIS assessment uses 1000x uncertainty for 10x animal-to-human extrapolation, 10x LOAEL-to-NOAEL extrapolation, and 10x for subchronic-to-chronic extrapolation. In this case study, our IATA resulted in a highly similar POD compared to the IRIS assessment, and an overall decrease in the uncertainty factors that needed to be applied. Our IATA approach worked well in this instance, and demonstrated several advantages by focusing on using a human-relevant in vitro model, data-driven POD modeling, and a net decrease in the overall risk assessment uncertainty factors, while maintaining the uncertainty associated with the data.

Dataset Information

A Genomic Approach to Warfarin Dose Prescription in Admixed Caribbean Hispanics

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