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 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.


CONCLUSIONS
ABCC2 haplotypes are associated with rPT induced by TDF in HIV-1-infected patients.
Izzedine
Hassane
H
Department of Nephrology, La Pitie-Salpetriere Hospital, Assistance Publique-Hopitaux de Paris, Universite Pierre et Marie Curie-Paris IV, 75013 Paris, France. hassan.izzedine@psl.aphp.fr
Hulot
Jean-Sebastien
JS
Villard
Eric
E
Goyenvalle
Catherine
C
Dominguez
Stephanie
S
Ghosn
Jade
J
Valantin
Marc Antoine
MA
Lechat
Philippe
P
Deray
And Gilbert
AG
D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives*; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000009:adverse effects*; D016022:Case-Control Studies; D005198:Fanconi Syndrome / Q000139:chemically induced* / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy*; D006239:Haplotypes; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D063065:Organophosphonates / Q000009:adverse effects*; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D013223:Statistics as Topic; D000068698:Tenofovir
D000225:Adenine; D019380:Anti-HIV Agents; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D063065:Organophosphonates; D000068698:Tenofovir; C000715087:ABCC2 protein, human; C073492:ABCC4 protein, human