Single Nucleotide Polymorphisms in ABCC2 Associate With Tenofovir-Induced Kidney Tubular Dysfunction in Japanese Patients With HIV-1 Infection: A Pharmacogenetic Study

Abstract

Tenofovir is a widely used antiretroviral drug although it can cause kidney tubular dysfunction (KTD). The aim of this study was to determine the association between polymorphisms in genes encoding drug transporters and KTD in Japanese patients treated with tenofovir. The association between tenofovir-induced KTD and 14 single nucleotide polymorphisms (SNPs) in the ABCC2, ABCC4, ABCC10, SCL22A6, and ABCB1 genes was investigated in 190 Japanese patients. KTD was diagnosed by the presence of at least 3 abnormalities in the following parameters: fractional tubular resorption of phosphate, fractional excretion of uric acid, urinary β2-microglobulin, urinary α1-microglobulin, and urinary N-acetyl-β-D-glucosaminidase. Genotyping was performed by allelic discrimination using TaqMan 5'-nuclease assays with standard protocols. Associations between genotypes and KTD were tested by univariate and multivariate logistic regression analyses. KTD was diagnosed in 19 of the 190 (10%) patients. Univariate and multivariate analyses showed a significant association between KTD and genotype CC at position -24 CC (adjusted odds ratio [OR], 20.08; 95% confidence interval [CI], 1.711-235.7; P= .017) and genotype AA at position 1249 (adjusted OR, 16.21; 95% CI, 1.630-161.1; P= .017) of ABCC2. Multivariate analysis showed higher adjusted OR for patients with both homozygotes (adjusted OR, 38.44; 95% CI, 2.051-720.4; P= .015). ABCC2 haplotype -24T and 1249G was a protective haplotype for KTD (OR, 0.098; 95% CI, .002-.603; P= .003 This is the first study of our knowledge to identify the association between SNPs in ABCC2 and tenofovir-induced KTD in an Asian population. Close monitoring of renal function is warranted in tenofovir-treated patients with these SNPs.