Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy

Background. 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. Methods. 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. Results. Six SNPs were identified in ABCC2. A significant allelic association between the 1249 GrA SNP and TDF-induced rPT was observed (odds ratio, 6.11 [95% confidence interval, 1.19-31.15];). ABCC2 haplotypes P < .02 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 poly-morphism and TDF-induced rPT in the present study. Conclusion. ABCC2 haplotypes are associated with rPT induced by TDF in HIV-1-infected patients.