Dataset Information

New genetic variant that might improve warfarin dose prediction in African Americans.

ABSTRACT: Variants in the CYP2C9 (i.e. *2 and *3) and VKORC1 (i.e. 1173C/T or -1639G/A) genes have been shown to influence warfarin dose requirements. However, these factors seem to explain less of the dose variability in African Americans who have a lower prevalence of the CYP2C9*2 and *3 and VKORC1 1173T alleles.In African Americans, the VKORC1 rs17886199 variant was statistically significantly associated with log-transformed warfarin maintenance dose, independent of the influence of VKORC1 1173C>T and CYP2C9*2 and *3. However, replication of our finding is needed to confirm the association of rs1786199 SNP in African Americans, since Limdi et al.[3] did not examine the effect of this SNP because the prevalence of the rs1786199 A-allele was too low.To raise hypotheses with regards to whether genetic variants in the VKORC1, CYP2C9, EPHX1, GGCX and ALB genes might influence warfarin dose in African Americans and Caucasians, independent of the effects of the VKORC1 1173C>T and CYP2C9*2 and *3 variants.From a prospective cohort study, we obtained additional DNA on 36 Caucasian and 22 African American warfarin users who reached maintenance dose and genotyped them for tagSNPs (r2<0.8) in VKORC1, EPHX1, GGCX and ALB genes, and one exonic CYP2C9 SNP. Linear regression models were fitted to estimate the relationship (P value) between log-transformed maintenance dose and each SNP and the amount of the warfarin dose variability accounted for by each SNP (partial R2).In African Americans, the VKORC1 rs17886199 A-allele was associated with a lower dose (GG=46.3 mg and GA=25.6 mg; P=0.002), independent of the VKORC1 1173C>T and CYP2C9*2 and *3 variants. Even after applying Bonferroni correction, the P value would still be considered statistically significant. The VKORC1 rs17886199 variant was not found in Caucasians. In Caucasians, the EPHX1 rs1051741 T-allele was associated with a lower dose (CC=41.3 mg and CT=30.0 mg; P=0.04). The latter was no longer statistically significant after applying Bonferroni correction.Our pilot study suggests that the VKORC1 rs17886199 variant could influence warfarin maintenance dose among African Americans, even after accounting for the influence of the VKORC1 1173C>T variant. Future studies with a larger sample size will be needed to confirm our findings.

SUBMITTER: Schelleman H

PROVIDER: S-EPMC2949912 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

New genetic variant that might improve warfarin dose prediction in African Americans.

Schelleman Hedi H Brensinger Colleen M CM Chen Jinbo J Finkelman Brian S BS Rieder Mark J MJ Kimmel Stephen E SE

British journal of clinical pharmacology 20100901 3

<h4>What is already known about this subject</h4>Variants in the CYP2C9 (i.e. *2 and *3) and VKORC1 (i.e. 1173C/T or -1639G/A) genes have been shown to influence warfarin dose requirements. However, these factors seem to explain less of the dose variability in African Americans who have a lower prevalence of the CYP2C9*2 and *3 and VKORC1 1173T alleles.<h4>What this study adds</h4>In African Americans, the VKORC1 rs17886199 variant was statistically significantly associated with log-transformed ...[more]

PMID: 20716240

Similar Datasets

Project description:Essentials Genetic variants controlling gene regulation have not been explored in pharmacogenomics. We tested liver expression quantitative trait loci for association with warfarin dose response. A novel predictor for increased warfarin dose response in African Americans was identified. Precision medicine must take into account population-specific variation in gene regulation.Background Warfarin is commonly used to control and prevent thromboembolic disorders. However, because of warfarin's complex dose-requirement relationship, safe and effective use is challenging. Pharmacogenomics-guided warfarin dosing algorithms that include the well-established VKORC1 and CYP2C9 polymorphisms explain only a small proportion of inter-individual variability in African Americans (AAs). Objectives We aimed to assess whether transcriptomic analyses could be used to identify regulatory variants associated with warfarin dose response in AAs. Patients/Methods We identified a total of 56 expression quantitative trait loci (eQTLs) for CYP2C9, VKORC1 and CALU derived from human livers and evaluated their association with warfarin dose response in two independent AA warfarin patient cohorts. Results We found that rs4889606, a strong cis-eQTL for VKORC1 (log10 Bayes Factor = 12.02), is significantly associated with increased warfarin daily dose requirement (? = 1.1; 95% confidence interval [CI] 0.46 to 1.8) in the discovery cohort (n = 305) and in the replication cohort (? = 1.04; 95% CI 0.33 -1.7; n = 141) after conditioning on relevant covariates and the VKORC1 -1639G>A (rs9923231) variant. Inclusion of rs4889606 genotypes, along with CYP2C9 alleles, rs9923231 genotypes and clinical variables, explained 31% of the inter-patient variability in warfarin dose requirement. We demonstrate different linkage disequilibrium patterns in the region encompassing rs4889606 and rs9923231 between AAs and European Americans, which may explain the increased dose requirement found in AAs. Conclusion Our approach of interrogating eQTLs identified in liver has revealed a novel predictor of warfarin dose response in AAs. Our work highlights the utility of leveraging information from regulatory variants mapped in the liver to uncover novel variants associated with drug response and the importance of population-specific research.

Dataset Information

New genetic variant that might improve warfarin dose prediction in African Americans.

Publications

New genetic variant that might improve warfarin dose prediction in African Americans.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets