title: Single nucleotide polymorphisms in ABCC2 associate with tenofovir-induced kidney tubular dysfunction in Japanese patients with HIV-1 infection: a pharmacogenetic study.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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
  
  
  CONCLUSIONS
  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.
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nishijima
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Komatsu
authors.forename: Koichiro
authors.initials: K
authors.lastname: Higasa
authors.forename: Misao
authors.initials: M
authors.lastname: Takano
authors.forename: Kiyoto
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Tsunefusa
authors.initials: T
authors.lastname: Hayashida
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Gatanaga
mesh_terms: D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives*; D000328:Adult; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D015658:HIV Infections / Q000150:complications*; D015497:HIV-1; D006801:Humans; D007564:Japan; D007674:Kidney Diseases / Q000139:chemically induced* / Q000150:complications / Q000235:genetics; D007684:Kidney Tubules / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D063065:Organophosphonates / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000068698:Tenofovir
chemical_list: D000225:Adenine; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D063065:Organophosphonates; D000068698:Tenofovir; C000715087:ABCC2 protein, human