Article

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: 6). 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 substitution leads to impaired ATPase activity which significantly influences cellular drug disposition[24]. Multiple studies have found differences in substrate levels intracellularly, drug activity, or toxicity with these polymorphisms2425262743]. In addition to its effect on the cellular disposition of several drugs, this same polymorphism has been implicated in various disease processes, including post-renal transplantation outcomes[44,45]non-alcoholic fatty liver disease[46], and intrahepatic cholestasis of pregnancy[47]. "
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    • "This discrepancy may reflect the fact that our patients constituted a patient group that had been receiving TDF for a relatively long interval without decreases of eGFR. In contrast, KTD has been reported to occur in numerous cases after 0.6 to 2.5 years of TDF exposure[20,22,25]. It should be noted here that it is a common practice in the hospital to stop TDF administration if patients show renal dysfunction after initiation on TDF-containing drugs. "
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