Pharmacogenetic Optimization of Anticoagulant Response (POAT) and Genetic and Environmental Determinants of Warfarin Response (GEDWR)
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ABSTRACT:
PROVIDER: PRJNA236403 | ENA |
REPOSITORIES: ENA
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Project description:<p>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.</p> <p>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).</p> <p>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.</p>
| phs000708 | dbGaP
Project description:Pharmacogenetic Optimization of Anticoagulant Response (POAT) and Genetic and Environmental Determinants of Warfarin Response (GEDWR)
| PRJNA236404 | ENA
Project description:Warfarin targets human vitamin K epoxide reductase (hVKOR), a redox enzyme in the membrane of endoplasmic reticulum (ER), to prevent the formation of blood clots. Although warfarin has been a popular medication since 1954, its mechanism of action is still unclear. A fundamental issue is the controversial orientation of transmembrane helices (TM) in hVKOR. Stable isotope-coded reagents were usedto label VKOR in free, mutated, and warfarin-binding states directly in the cellular environment, followed by LC-MS/MS bottom-up approach to investigate the warfarin binding mechanism.
2017-03-30 | PXD003774 | Pride
Project description:Pharmacogenomics of Warfarin in Hispanics and Latinos
| PRJNA887524 | ENA
Project description:Gene Discovery for Warfarin-Related Intracerebral Hemorrhage
| PRJNA75953 | ENA
Project description:Vitamin K epoxide reductase (VKOR) drives the vitamin K cycle, activating vitamin K-dependent blood clotting factors. VKOR is also the target of the widely used anticoagulant drug, warfarin. Despite VKOR’s pivotal role in coagulation, its structure and active site remain poorly understood. Here, we used multiplexed, sequencing-based assays to measure the effects of 2,695 VKOR missense variants on abundance and 697 variants on activity in cultured human cells.
2020-08-10 | GSE149922 | GEO
Project description:Genome-wide association study of Warfarin dosing in 714 British, recruited in Liverpool and Birmingham. Three phenotypes were investigated: warfarin mean dose, warfarin mean stable dose, and INR over 4 during first week of treatment. Stability was defined by at least three INR measurements within target in a three week period. The samples were genotyped on the Illumina 610K chip and imputed using Impute v2.1, with a combined filtered set composed of HapMap 3 release 2 and 1000 genomes pilot 1 CEU.
| EGAS00001001130 | EGA
Project description:<p>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.</p>
| phs001496 | dbGaP