Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy

Department of Nephrology, La Pitie-Salpetriere Hospital, Assistance Publique-Hopitaux de Paris, Universite Pierre et Marie Curie-Paris IV, 75013 Paris, France.
The Journal of Infectious Diseases (Impact Factor: 5.78). 12/2006; 194(11):1481-91. DOI: 10.1086/508546
Source: PubMed

ABSTRACT Tenofovir disoproxil fumarate (TDF) may induce renal proximal tubulopathy (rPT). There are no data on pharmacogenomic predictors of rPT in the genes encoding the multidrug-resistance protein (MRP) 2 and MRP4 transporters.
Mutational screening of the genes for MRP2 (ABCC2) and MRP4 (ABCC4) was performed using genomic DNA from 13 human immunodeficiency virus type 1 (HIV-1)-infected patients (group 1) presenting with TDF-induced rPT. Concomitantly, 17 unrelated HIV-1-infected patients who had received TDF therapy and who did not have rPT (group 2) were included in a case-control analysis, to assess the influence of single-nucleotide polymorphisms (SNPs) identified in ABCC2 and ABCC4.
Six SNPs were identified in ABCC2. A significant allelic association between the 1249 G-->A SNP and TDF-induced rPT was observed (odds ratio, 6.11 [95% confidence interval, 1.19-31.15]; P<.02). ABCC2 haplotypes were significantly associated with the onset of TDF-induced rPT--CATC appeared to be a predisposing haplotype, as it was found in 40.9% of the group 1 case patients and in 13.7% of the group 2 control subjects (P<.01), whereas CGAC appeared to be a protective haplotype, as it was not observed in the group 1 case patients but was present in 20.2% of the group 2 control subjects (P<.01). No association was observed between ABCC4 polymorphism and TDF-induced rPT in the present study.
ABCC2 haplotypes are associated with rPT induced by TDF in HIV-1-infected patients.

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    • "This contrast with the higher frequency of Fanconi syndrome in HIV patients exposed to TDF where the risk of kidney injury associated to TDF is most likely multifactorial , and exaggerated by older age, lower body weight, pre-existing renal impairment, concomitant use of nephrotoxic medications and such co-morbidities as diabetes or arterial hypertension [4]. However, the association of Fanconi syndrome with HIV may also depend on an interaction with the multidrug-resistance proteins 2 (MRP2) implicated in drug efflux at the apical surface of the proximal tubule whose altered function may lead to drug accumulation within tubular epithelial cells resulting in kidney tubular dysfunction [8] [9] [10]. Indeed, genetic polymorphisms of this protein encoded by the adenosine triphosphate-binding cassette (ABC) gene ABCC2, is strongly associated with development of kidney tubular dysfunction in TDF exposed individuals [9] [10]. "
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    Journal of Clinical Virology 10/2014; 61(4). DOI:10.1016/j.jcv.2014.09.016 · 3.47 Impact Factor
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    • "were genotyped by direct sequencing. PCR was carried out in a total volume of 50 μL containing 100 ng of total DNA, 10 pmol of each primer (Table 1) [24] "
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    ABSTRACT: MRP2 encoded by ABCC2 gene is involved in the secretion of numerous drugs and endogenous substrates. Patients with Dubin-Johnson syndrome due to mutation in ABCC2 gene have elevated urinary coproporphyrin ratio (UCP I/(I + III)). Here we investigated whether this ratio could serve as a biomarker of MRP2 function. Phenotype-genotype relationships were studied in 74 healthy subjects by measuring individual UCP I/(I + III) ratio obtained on 24-hour urine and by analyzing five common SNPs in ABCC2 gene. The UCP I/(I + III) ratio varied from 14.7% to 46.0% in our population. Subjects with 3972TT genotype had a higher ratio (P = .04) than those carrying the C allele. This higher UCP I/(I + III) ratio was correlated with a higher level of isomer I excretion. This study provides a proof of concept that UCP I/(I + III) ratio can be used as a biomarker of MRP2 function in clinical studies as it provides quantitative information about the in vivo activity of MRP2 in a given patient.
    BioMed Research International 03/2011; 2011:498757. DOI:10.1155/2011/498757 · 2.71 Impact Factor
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    • "Interestingly, the 4131T>G variant is in the 3'-untranslated region (UTR) of the gene, while the 3724G>A variant is synonymous and there is no clear mechanism explaining these effects. In another study, no association was observed between two non-synonymous and seven synonymous ABCC4 variants and tenofovir disoproxil fumarate-induced renal proximal tubulopathy (Izzedine et al., 2006). Most recently, 74 genetic variants in ABCC4 were shown to have no effect on MRP4 mRNA and protein expression in Caucasian cholestatic and noncholestatic patients (Gradhand et al., 2008). "
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    ABSTRACT: ABCC4 encodes multidrug resistance protein 4 (MRP4), a member of the ATP-binding cassette family of membrane transporters involved in the efflux of endogenous and xenobiotic molecules. The aims of this study were to identify single nucleotide polymorphisms of ABCC4 and to functionally characterize selected nonsynonymous variants. Resequencing was performed in a large ethnically diverse population. Ten nonsynonymous variants were selected for analysis of transport function based on allele frequencies and evolutionary conservation. The reference and variant MRP4 cDNAs were constructed by site-directed mutagenesis and transiently transfected into human embryonic kidney cells (HEK 293T). The function of MRP4 variants was compared by measuring the intracellular accumulation of two antiviral agents, azidothymidine (AZT) and adefovir (PMEA). A total of 98 variants were identified in the coding and flanking intronic regions of ABCC4. Of these, 43 variants are in the coding region, and 22 are nonsynonymous. In a functional screen of ten variants, there was no evidence for a complete loss of function allele. However, two variants (G187W and G487E) showed a significantly reduced function compared to reference with both substrates, as evidenced by higher intracellular accumulation of AZT and PMEA compared to the reference MRP4 (43 and 69% increase in accumulation for G187W compared with the reference MRP4, with AZT and PMEA, respectively). The G187W variant also showed decreased expression following transient transfection of HEK 293T cells. Further studies are required to assess the clinical significance of this altered function and expression and to evaluate substrate specificity of this functional change.
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