Dataset Information

The Impact of Genetic and Non-Genetic Factors on Warfarin Dose Prediction in MENA Region: A Systematic Review.

ABSTRACT:

Background

Warfarin is the most commonly used oral anticoagulant for the treatment and prevention of thromboembolic disorders. Pharmacogenomics studies have shown that variants in CYP2C9 and VKORC1 genes are strongly and consistently associated with warfarin dose variability. Although different populations from the Middle East and North Africa (MENA) region may share the same ancestry, it is still unclear how they compare in the genetic and non-genetic factors affecting their warfarin dosing.

Objective

To explore the prevalence of CYP2C9 and VKORC1 variants in MENA, and the effect of these variants along with other non-genetic factors in predicting warfarin dose.

Methods

In this systematic review, we included observational cross sectional and cohort studies that enrolled patients on stable warfarin dose and had the genetics and non-genetics factors associated with mean warfarin dose as the primary outcome. We searched PubMed, Medline, Scopus, PharmGKB, PHGKB, Google scholar and reference lists of relevant reviews.

Results

We identified 17 studies in eight different populations: Iranian, Israeli, Egyptian, Lebanese, Omani, Kuwaiti, Sudanese and Turkish. Most common genetic variant in all populations was the VKORC1 (-1639G>A), with a minor allele frequency ranging from 30% in Egyptians and up to 52% and 56% in Lebanese and Iranian, respectively. Variants in the CYP2C9 were less common, with the highest MAF for CYP2C9*2 among Iranians (27%). Variants in the VKORC1 and CYP2C9 were the most significant predictors of warfarin dose in all populations. Along with other genetic and non-genetic factors, they explained up to 63% of the dose variability in Omani and Israeli patients.

Conclusion

Variants of VKORC1 and CYP2C9 are the strongest predictors of warfarin dose variability among the different populations from MENA. Although many of those populations share the same ancestry and are similar in their warfarin dose predictors, a population specific dosing algorithm is needed for the prospective estimation of warfarin dose.

SUBMITTER: Bader LA

PROVIDER: S-EPMC5167425 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Publications

The Impact of Genetic and Non-Genetic Factors on Warfarin Dose Prediction in MENA Region: A Systematic Review.

Bader Loulia Akram LA Elewa Hazem H

PloS one 20161219 12

<h4>Background</h4>Warfarin is the most commonly used oral anticoagulant for the treatment and prevention of thromboembolic disorders. Pharmacogenomics studies have shown that variants in CYP2C9 and VKORC1 genes are strongly and consistently associated with warfarin dose variability. Although different populations from the Middle East and North Africa (MENA) region may share the same ancestry, it is still unclear how they compare in the genetic and non-genetic factors affecting their warfarin do ...[more]

PMID: 27992547

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Project description: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.

Dataset Information

The Impact of Genetic and Non-Genetic Factors on Warfarin Dose Prediction in MENA Region: A Systematic Review.

Background

Objective

Methods

Results

Conclusion

Publications

The Impact of Genetic and Non-Genetic Factors on Warfarin Dose Prediction in MENA Region: A Systematic Review.

Similar Datasets

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