Association of the C3435T polymorphism of the MDR1 gene and therapeutic doses of warfarin in thrombophilic patients

Almeida, Vinicius Santos; Ferreira, Alessandro Clayton de Souza; Ribeiro, Daniel Dias; Borges, Karina Braga Gomes; Fernandes, André Almeida; Godard, Ana Lúcia Brunialti

doi:10.1111/j.1538-7836.2011.04452.x

Cited by 21 publications

(13 citation statements)

References 10 publications

(10 reference statements)

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“…The ABCB1-3435CC genotype has been associated with a lower VKA dose [43,44], whereas the warfarin dose was found to be 24% lower in patients heterozygous for ABCB1 haplotype D, which includes C3435T nucleotide exchange [41]. In our patients, the ABCB1 gene polymorphism showed no influence on stable ACN dose and was not included in the final model.…”

Section: Discussioncontrasting

confidence: 46%

“…The influence of ABCB1 C3435T on VKAs dose requirements is controversial [41,43,44]. The ABCB1-3435CC genotype has been associated with a lower VKA dose [43,44], whereas the warfarin dose was found to be 24% lower in patients heterozygous for ABCB1 haplotype D, which includes C3435T nucleotide exchange [41].…”

Section: Discussionmentioning

confidence: 96%

“…The influence of P-glycoprotein on ACN distribution and pharmacological action has not yet been examined, although similar pharmacodynamics might be expected, given the structural similarities between ACN and warfarin [43]. Very few studies have been published on the influence of ABCB1 C3435T on VKA dose requirements, and the results have been controversial [41,43,44].…”

Section: Introductionmentioning

confidence: 95%

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Prediction of stable acenocoumarol dose by a pharmacogenetic algorithm

Jiménez-Varo

Cañadas-Garre

Gutiérrez-Pimentel

et al. 2014

Pharmacogenetics and Genomics

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Section: Discussioncontrasting

confidence: 46%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 95%

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Prediction of stable acenocoumarol dose by a pharmacogenetic algorithm

Jiménez-Varo

Cañadas-Garre

Gutiérrez-Pimentel

et al. 2014

Pharmacogenetics and Genomics

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“…In separate publications, the same group concluded that “genetic information on CYP2C9 and VKORC1 is important both for the initial dose‐finding phase and during maintenance treatment with warfarin”, “amiodarone influences warfarin maintenance dose” while not being associated with adverse events and CYP4F2 rs2108622 has no effect of warfarin dose requirements in their patients, whereas the ABCB1 c.3435T allele marginally affected the dose requirements . The direction of the latter effect was opposite to previously reported higher warfarin dose requirement in thrombophilic patients with the ABCB1 c.3435T allele . A recent study concluded that ABCB1 and CYP4F2 polymorphisms improve by 2.6% the coefficient of determination of warfarin dosing algorithms .…”

Section: Resultsmentioning

confidence: 63%

Pharmacogenomics research and clinical implementation in Brazil

Rodrigues‐Soares

Suarez‐Kurtz

2019

Basic Clin Pharma Tox

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We searched PubMed entries and the Lattes database of Brazilian Pharmacogenetics Network investigators, for pharmacogenetic/genomic (PGx) studies in the Brazilian population, focusing on the drugs and genes included in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. Warfarin was the most extensively studied drug in a PGx context: a genomewide association study targeting warfarin stable dose identified significant signals in VKORC1 and CYP2C9, several PGx dosing algorithms were developed based on these and other genes, and the implications of population admixture on extrapolation of dosing recommendations in the CPIC guidelines were examined. A study in renal transplanted patients disclosed association of CYP3A5*6 and CYP3A5*7 with tacrolimus dosing, which led to addition of these variants to CYP3A5*3 in the CPIC tacrolimus guideline. Studies verified predisposition of HIV-positive carriers of UGT1A1*28 to severe atazanavir-induced hyperbilirubinaemia, intolerance to 5-fluorouracyl in gastrointestinal cancer patients with deleterious DPYD variants, failure of HCV-infected carriers of IFNL3 rs12979860 to obtain a sustained viral response to PEG-IFN-α, and hypersensitivity reactions to abacavir in HIV-positive carriers of HLA-B*57:01. No prospective analyses of drug therapy outcomes or cost-effectiveness assessments of PGx-guided therapy were found. In conclusion, the limited adoption of PGx-informed drug prescription in Brazil reflects combination of recognized barriers to PGx implementation worldwide plus factors specific to the Brazilian population. The latter include rarity/absence of genetic variants on which international PGx guidelines are based (eg HLA-B*15.02 for phenytoin and carbamazepine) and the caveat of extrapolating to the admixed Brazilian population, guidelines based on categorical variables, such as continental ancestry (eg warfarin guidelines), "race" or ethnicity.

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“…More recently, the ABCB1 3435C>T variant was associated with warfarin resistance in a Brazilian population [33]. In contrast, common VKORC1 as well as CYP2C9 SNPs correlate with the usual warfarin dose variability that occurs in the general population.…”

Section: Discussionmentioning

confidence: 99%

Association of the GGCX (CAA)16/17 repeat polymorphism with higher warfarin dose requirements in African Americans

Cavallari

Perera

Wadelius

et al. 2012

Pharmacogenetics and Genomics

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Objective Little is known about genetic contributors to higher than usual warfarin dose requirements, particularly for African Americans. This study tested the hypothesis that the γ-glutamyl carboxylase (GGCX) genotype contributes to warfarin dose requirements >7.5 mg/day in an African American population. Methods A total of 338 African Americans on a stable dose of warfarin were enrolled. The GGCX rs10654848 (CAA)n, rs12714145 (G>A), and rs699664 (p.R325Q); VKORC1 c.-1639G>A and rs61162043; and CYP2C9*2, *3, *5, *8, *11, and rs7089580 genotypes tested for their association with dose requirements >7.5 mg/day alone and in the context of other variables known to influence dose variability. Results The GGCX rs10654848 (CAA) 16 or 17 repeat occurred at a frequency of 2.6% in African Americans and was overrepresented among patients requiring >7.5mg/day versus those who required lower doses (12% vs 3%, p=0.003; odds ratio 4.0, 95% CI, 1.5–10.5). The GGCX rs10654848 genotype remained associated with high dose requirements on regression analysis including age, body size, and VKORC1 genotype. On linear regression, the GGCX rs10654848 genotype explained 2% of the overall variability in warfarin dose in African Americans. An examination of the GGCX rs10654848 genotype in warfarin-treated Caucasians revealed a (CAA)16 repeat allele frequency of only 0.27% (p=0.008 compared to African Americans). Conclusion These data support the GGCX rs10654848 genotype as a predictor of higher than usual warfarin doses in African Americans, who have a 10-fold higher frequency of the (CAA)16/17 repeat compared to Caucasians.

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Association of the C3435T polymorphism of the MDR1 gene and therapeutic doses of warfarin in thrombophilic patients

Cited by 21 publications

References 10 publications

Prediction of stable acenocoumarol dose by a pharmacogenetic algorithm

Prediction of stable acenocoumarol dose by a pharmacogenetic algorithm

Pharmacogenomics research and clinical implementation in Brazil

Association of the GGCX (CAA)16/17 repeat polymorphism with higher warfarin dose requirements in African Americans

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