Novel
            <i>CYP2C9</i>
            and
            <i>VKORC1</i>
            Gene Variants Associated with Warfarin Dosage Variability in the South African Black Population

Mitchell, Cathrine; Gregersen, Nerine; Krause, Amanda

doi:10.2217/pgs.11.36

Cited by 49 publications

(46 citation statements)

References 39 publications

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“…In Caucasian patients this SNP had no relationship to dose [28], whereas an increase in warfarin dosage was described in a South African black population [29]. Our study suggests that this polymorphism increases the requirements for acenocoumarol with a clear genotype-dose correlation.…”

Section: Discussionmentioning

confidence: 50%

Novel Associations of VKORC1 Variants with Higher Acenocoumarol Requirements

et al. 2013

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BackgroundAlgorithms combining both clinical and genetic data have been developed to improve oral anticoagulant therapy. Three polymorphisms in two genes, VKORC1 and CYP2C9, are the main coumarin dose determinants and no additional polymorphisms of any relevant pharmacogenetic importance have been identified.ObjectivesTo identify new genetic variations in VKORC1 with relevance for oral anticoagulant therapy.Methods and Results3949 consecutive patients taking acenocoumarol were genotyped for the VKORC1 rs9923231 and CY2C9* polymorphisms. Of these, 145 patients with a dose outside the expected range for the genetic profile determined by these polymorphisms were selected. Clinical factors explained the phenotype in 88 patients. In the remaining 57 patients, all with higher doses than expected, we sequenced the VKORC1 gene and genetic changes were identified in 14 patients. Four patients carried VKORC1 variants previously related to high coumarin doses (L128R, N = 1 and D36Y, N = 3).Three polymorphisms were also detected: rs17878544 (N = 5), rs55894764 (N = 4) and rs7200749 (N = 2) which was in linkage disequilibrium with rs17878544. Finally, 2 patients had lost the rs9923231/rs9934438 linkage. The prevalence of these variations was higher in these patients than in the whole sample. Multivariate linear regression analysis revealed that only D36Y and rs55894764 variants significantly affect the dose, although the improvement in the prediction model is small (from 39% to 40%).ConclusionOur strategy identified novel associations of VKORC1 variants with higher acenocoumarol doses albeit with a low effect size. Further studies are necessary to test their influence on the VKORC1 function and the cost/benefit of their inclusion in pharmacogenetic algorithms.

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Section: Discussionmentioning

confidence: 50%

Novel Associations of VKORC1 Variants with Higher Acenocoumarol Requirements

et al. 2013

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“…This variant had been previously reported as affecting warfarin resistance in a small cohort of South African descent; however, in our model, the variant had a P value of .311. 36 For CYP2C9, we found no novel nonsynonymous variants.…”

Section: 3435mentioning

confidence: 73%

Genetic variant in folate homeostasis is associated with lower warfarin dose in African Americans

Daneshjou

Gamazon

Burkley

et al. 2014

Blood

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Key Points• A population-specific genetic variant involved in folate homeostasis is associated with lower warfarin dose in African Americans.The anticoagulant warfarin has >30 million prescriptions per year in the United States. Doses can vary 20-fold between patients, and incorrect dosing can result in serious adverse events. Variation in warfarin pharmacokinetic and pharmacodynamic genes, such as CYP2C9 and VKORC1, do not fully explain the dose variability in African Americans.To identify additional genetic contributors to warfarin dose, we exome sequenced 103 African Americans on stable doses of warfarin at extremes (£35 and ‡49 mg/week). We found an association between lower warfarin dose and a population-specific regulatory variant, rs7856096 (P 5 1.82 3 10 28 , minor allele frequency 5 20.4%), in the folate homeostasis gene folylpolyglutamate synthase (FPGS). We replicated this association in an independent cohort of 372 African American subjects whose stable warfarin doses represented the full dosing spectrum (P 5 .046). In a combined cohort, adding rs7856096 to the International Warfarin Pharmacogenetic Consortium pharmacogenetic dosing algorithm resulted in a 5.8 mg/week (P 5 3.93 3 10 25 ) decrease in warfarin dose for each allele carried. The variant overlaps functional elements and was associated (P 5 .01) with FPGS gene expression in lymphoblastoid cell lines derived from combined HapMap African populations (N 5 326). Our results provide the first evidence linking genetic variation in folate homeostasis to warfarin response. (Blood. 2014;124(14):2298-2305

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“…[19] Recent data also provide further evidence of reduced warfarin clearance and dose requirements with the *5, *6 , and *11 alleles. [30, 33]…”

Section: Discussionmentioning

confidence: 99%

Poor warfarin dose prediction with pharmacogenetic algorithms that exclude genotypes important for African Americans

Drozda

Wong

Patel

et al. 2015

Pharmacogenetics and Genomics

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Objectives Recent clinical trial data cast doubt on the utility of genotype-guided warfarin dosing, specifically showing worse dosing with a pharmacogenetic versus clinical dosing algorithm in African Americans. However, many genotypes important in African Americans were not accounted for. We aimed to determine if omission of the CYP2C9*5, *6, *8, *11 alleles and rs12777823 G>A genotype affects performance of dosing algorithms in African Americans. Methods In a cohort of 274 warfarin-treated African Americans, we examined the association between the CYP2C9*5, *6, *8, *11 alleles and rs12777823 G>A genotype and warfarin dose prediction error with pharmacogenetic algorithms used in clinical trials. Results The warfarindosing.org algorithm over-estimated doses by a median (IQR) of 1.2 (0.02 to 2.6) mg/day in rs12777823 heterozygotes (p<0.001 for predicted versus observed dose), 2.0 (0.6 to 2.8) mg/day in rs12777823 variant homozygotes (p=0.004), and 2.2 (0.5 to 2.9) mg/day in carriers of a CYP2C9 variant (p<0.001). The International Warfarin Pharmacogenetics Consortium (IWPC) algorithm under-dosed warfarin by 0.8 (−2.3 to 0.4) mg/day for patients with the rs12777823 GG genotype (p<0.001) and over-dosed warfarin by 0.7 (−0.4 to 1.9) mg/day in carriers of a variant CYP2C9 allele (p=0.04). Modifying the warfarindosing.org algorithm to adjust for variants important in African Americans led to better dose prediction than either the original warfarindosing.org (p<0.01) or IWPC (p<0.01) algorithm. Conclusions These data suggest that, when providing genotype-guided warfarin dosing, failure to account for variants important in African Americans leads to significant dosing error in this population.

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Novel CYP2C9 and VKORC1 Gene Variants Associated with Warfarin Dosage Variability in the South African Black Population

Cited by 49 publications

References 39 publications

Novel Associations of VKORC1 Variants with Higher Acenocoumarol Requirements

Novel Associations of VKORC1 Variants with Higher Acenocoumarol Requirements

Genetic variant in folate homeostasis is associated with lower warfarin dose in African Americans

Poor warfarin dose prediction with pharmacogenetic algorithms that exclude genotypes important for African Americans

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