Evaluation of the effects of VKORC1 polymorphisms and haplotypes, CYP2C9 genotypes, and clinical factors on warfarin response in Sudanese patients

Shrif, Nassr Eldin M.A.; Won, Hong‐Hee; Lee, Seung Tae; Park, Jun‐Hee; Kim, Ka-Kyung; Kim, Minji; Kim, Seonwoo; Lee, Soo-Youn; Ki, Chang‐Seok; Osman, Ihsan M.; Rhman, Enaam A.; Ali, Ibtisam; Idris, Mohamed Na; Kim, Jong-Won

doi:10.1007/s00228-011-1060-1

Cited by 43 publications

(40 citation statements)

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“…CYP2C9 *8 (rs9332094) is another rare variant that affects around 12% of African Americans and has been associated with reduced S -warfarin clearance [54]. This SNP was only investigated in two populations of MENA; Egyptians and Sudanese [12, 41]. Despite some of the similarities found between these two populations and African Americans, the CYP2C9*8 did not shown any significant association with warfarin dose requirements in Egyptians and Sudanese as it did in African Americans.…”

Section: Discussionmentioning

confidence: 99%

“…Despite some of the similarities found between these two populations and African Americans, the CYP2C9*8 did not shown any significant association with warfarin dose requirements in Egyptians and Sudanese as it did in African Americans. This might be in part due the fact that this variant was not very common in these populations, it showed a MAF of 0.008 and 0.01 in Egyptians and Sudanese, respectively [12, 41]. On the other hand, the frequencies of CYP2C9 *2 and *3 and VKORC1 (3673G>A) reported in Turkish [43] were closer to Caucasians than to Asians and African Americans [1].…”

Section: Discussionmentioning

confidence: 99%

“…Shrif and colleagues were able to identify four different SNPs downstream from the VKORC1 gene (rs7199949, rs11865038, rs11864839, and rs750952). These SNPs were found to be located in newly identified gene which is only 2 kb downstream from the VKORC1 gene in the same reverse strand named: POL3S (polyserase 3S) [41]. Amino acid sequences of the POL3S are highly conserved among humans, chimpanzees, dogs, cows, and mice [55].…”

Section: Discussionmentioning

confidence: 99%

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

Bader

Elewa

2016

PLoS ONE

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BackgroundWarfarin 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.ObjectiveTo 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.MethodsIn 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.ResultsWe 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.ConclusionVariants 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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Bader

Elewa

2016

PLoS ONE

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“…From these results, given the smaller range of variant allele frequency for CYP2C9 to that of VKORC1, it is apparent that the association in warfarin therapy stability is larger for VKORC1 than for CYP2C9 29,30 . By taking a general look at the ethnicity versus frequencies of both genes, we found that 22% of all Sudanese patients were without any of the variant alleles of both CYP2C9*2 and VKORC1-1639G>A, that means having neither heterozygous nor homozygous mutant genotypes of the tow genes studied.…”

Section: Genetic and Non-genetic Factors Association With Warfarin Lomentioning

confidence: 95%

Genetic and Non-Genetic Factors Association with Warfarin Long Term Therapy Stability in Sudan

Aldahab¹,

Elkhawad²

2016

AJPRHC

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Anticoagulation with warfarin is characterized by a wide inter-individual variations in dose requirements and INR (International Normalised Ratio) stability, as there are evidences that warfarin response variability is associated with CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) and VKORC1 (Vitamin K epoxide reductase complex1) genetic polymorphisms. Carriers of CYP2C9*2 and VKORC11639G>A variant alleles are at greater risk of unstable anticoagulation therapy. Objectives: This retrospective case control study was directed to analyze the impact of genetic and non-genetic factors on warfarin therapy in Sudanese out-patients who were on long term warfarin therapy. Method: 118 Sudanese outpatients receiving warfarin treatment for at least six months, were interviewed for their non-genetic factors that included age, sex, indication for warfarin therapy, compliance, Vitamin K rich foods intake and concomitant drug therapy, in addition to their blood samples which were taken for DNA extraction and genotyping of CYP2C9*2 and VKORC11639G>A gene polymorphisms to study the genetic factors. INR stability % index was calculated, accordingly patients were classified into 2 groups, stable and unstable groups. Results: The frequencies of VKORC11639G>A alleles in Sudanese out-patients who were on long term warfarin therapy were 70.3% and 29.7% for the VKORC1/G and VKORC1/A alleles respectively. The frequencies of CYP2C9*2 alleles in Sudanese out-patients were 92.4% and 7.6% for CYP2C9*1 and CYP2C9*2 alleles respectively. Variables associated with low INR stability were VKCOR1/AA genotype (p-value = 0.028) and sex (p = 0.017). Variables that showed no association with INR stability were age (p-value = 0.259), compliance (p-value = 0.058). Vitamin K rich foods intake (p-value = 0.743), and mean stable warfarin dose (p-value = 0.439). Conclusion: Polymorphism in warfarin drug target gene VKORC1-11639G>A and sex are important elements of INR stability in Sudanese out-patients on long term warfarin therapy.

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“…Overcoagulation causes bleeding episodes, with intracranial hemorrhage being one of the most catastrophic. The effects of genetic polymorphisms in its metabolizing enzyme, CYP2C9, as well as the VKORC1 gene's sensitivity to warfarin have been shown in many studies to significantly affect the dosing requirements [47,48,49,50,51], with the CYP2C9*1/*1 genotype associated with a higher maintenance dose compared to the genotype containing CYP2C9*2 or *3 alleles. There are about 28 known polymorphisms for the VKORC1 gene to date, with the 1639G>A polymorphism being most clinically significant.…”

Section: Cyp2c9 and Vkorc1: Warfarinmentioning

confidence: 99%

The Importance of Ethnicity Definitions and Pharmacogenomics in Ethnobridging

et al. 2013

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Evaluation of the effects of VKORC1 polymorphisms and haplotypes, CYP2C9 genotypes, and clinical factors on warfarin response in Sudanese patients

Abstract: Our data revealed that VKORC1 and CYP2C9 polymorphisms are important factors that influence warfarin dose response in Sudanese patients. Our data suggest that combinations of the SNPs may improve predictions of warfarin dose requirements.

Cited by 43 publications

References 47 publications

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

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

Genetic and Non-Genetic Factors Association with Warfarin Long Term Therapy Stability in Sudan

The Importance of Ethnicity Definitions and Pharmacogenomics in Ethnobridging

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