A Genomic Approach to Warfarin Dose Prescription in Admixed Caribbean Hispanics
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PROVIDER: PRJNA421230 | ENA |
REPOSITORIES: ENA
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Project description:A Genomic Approach to Warfarin Dose Prescription in Admixed Caribbean Hispanics
| PRJNA421231 | ENA
Project description:Pharmacogenomics of Warfarin in Hispanics and Latinos
| PRJNA887524 | ENA
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
Project description: Not available
| S-EPMC6987072 | biostudies-literature
Project description:Recently genome-wide association studies have identified significant association between Alzheimer’s disease and variations in CLU, PICALM, BIN1, CR1, MS4A4/MS4A6E, CD2AP, CD33, EPHA1 and ABCA7. However, the pathogenic variants in these loci have not yet been found. We conducted a genome-wide scan for large copy number variations (CNVs) in a dataset of Caribbean Hispanic origin (554 controls and 559 cases with late-onset Alzheimer’s disease) that was previously investigated in a SNP-based genome-wide association study using Illumina HumanHap 650Y platform. We ran four CNV calling algorithms and analyzed rare large CNVs (>100 Kb) to obtain high-confidence calls that were detected by at least two algorithms. In total, 734 such CNVs were observed in our dataset. Global burden analyses did not reveal significant differences between cases and controls in CNV rate, distribution of deletions or duplications, total or average CNV size; and number of genes affected by CNVs. However, we observed a nominal association between Alzheimer’s disease and a ~470 Kb duplication on chromosome15q11.2 (P=0.037). This duplication, encompassing up to five genes (TUBGCP5, CYFIP1, NIPA2, NIPA1 and WHAMML1) was present in 10 cases (2.6%) and 3 controls (0.8%). The dosage increase of CYFIP1 and NIPA1 genes was further confirmed by quantitative PCR. The current study did not detect CNVs (including common CNVs) that affect novel Alzheimer’s disease loci reported by large genome-wide association studies. However, since the array technology used in our study has limitations in detecting small CNVs, future studies must carefully assess novel AD associated genes for the presence of disease related CNVs. Case-control analysis, screening of large copy number variation in 559 Alzheimer cases and 554 control subjects of Caribbean Hispanic ancestry
2012-04-30 | E-GEOD-33528 | biostudies-arrayexpress
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: Not available
| S-EPMC4706412 | biostudies-literature
Project description:Recently genome-wide association studies have identified significant association between Alzheimer’s disease and variations in CLU, PICALM, BIN1, CR1, MS4A4/MS4A6E, CD2AP, CD33, EPHA1 and ABCA7. However, the pathogenic variants in these loci have not yet been found. We conducted a genome-wide scan for large copy number variations (CNVs) in a dataset of Caribbean Hispanic origin (554 controls and 559 cases with late-onset Alzheimer’s disease) that was previously investigated in a SNP-based genome-wide association study using Illumina HumanHap 650Y platform. We ran four CNV calling algorithms and analyzed rare large CNVs (>100 Kb) to obtain high-confidence calls that were detected by at least two algorithms. In total, 734 such CNVs were observed in our dataset. Global burden analyses did not reveal significant differences between cases and controls in CNV rate, distribution of deletions or duplications, total or average CNV size; and number of genes affected by CNVs. However, we observed a nominal association between Alzheimer’s disease and a ~470 Kb duplication on chromosome15q11.2 (P=0.037). This duplication, encompassing up to five genes (TUBGCP5, CYFIP1, NIPA2, NIPA1 and WHAMML1) was present in 10 cases (2.6%) and 3 controls (0.8%). The dosage increase of CYFIP1 and NIPA1 genes was further confirmed by quantitative PCR. The current study did not detect CNVs (including common CNVs) that affect novel Alzheimer’s disease loci reported by large genome-wide association studies. However, since the array technology used in our study has limitations in detecting small CNVs, future studies must carefully assess novel AD associated genes for the presence of disease related CNVs.
2012-05-01 | GSE33528 | GEO
Project description: Not available
| S-EPMC5461284 | biostudies-literature
Project description:Adopting a Precision Medicine Paradigm in Puerto Rico: leveraging ancestral diversity to identify predictors of clopidogrel response in Caribbean Hispanics
| PRJNA948119 | ENA