Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy

J Infect Dis. 2006 Dec 1;194(11):1481-91. doi: 10.1086/508546. Epub 2006 Oct 26.

Abstract

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 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.

Conclusion: ABCC2 haplotypes are associated with rPT induced by TDF in HIV-1-infected patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / adverse effects
  • Adenine / analogs & derivatives*
  • Adult
  • Aged
  • Anti-HIV Agents / adverse effects*
  • Case-Control Studies
  • Fanconi Syndrome / chemically induced*
  • Fanconi Syndrome / genetics*
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • HIV Infections / complications
  • HIV Infections / drug therapy*
  • Haplotypes*
  • Humans
  • Male
  • Membrane Transport Proteins / genetics*
  • Middle Aged
  • Multidrug Resistance-Associated Proteins / genetics*
  • Organophosphonates / adverse effects*
  • Point Mutation
  • Polymorphism, Single Nucleotide
  • Statistics as Topic
  • Tenofovir

Substances

  • ABCC4 protein, human
  • Anti-HIV Agents
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Proteins
  • Organophosphonates
  • multidrug resistance-associated protein 2
  • Tenofovir
  • Adenine