title: Genetic variants of ABCC10, a novel tenofovir transporter, are associated with kidney tubular dysfunction.
abstract: BACKGROUND
  Tenofovir (TFV) causes kidney tubular dysfunction (KTD) in some patients, but the mechanism is poorly understood. Genetic variants in TFV transporters are implicated; we explored whether ABCC10 transports TFV and whether ABCC10 single-nucleotide polymorphisms (SNPs) are associated with KTD.
  
  
  METHODS
  TFV accumulation was assessed in parental and ABCC10-transfected HEK293 cells (HEK293-ABCC10), CD4(+) cells and monocyte-derived macrophages (MDMs). Substrate specificity was confirmed by cepharanthine (ABCC10 inhibitor) and small interfering RNA (siRNA) studies. Fourteen SNPs in ABCC10 were genotyped in human immunodeficiency virus-positive patients with KTD (n = 19) or without KTD (controls; n = 96). SNP and haplotype analysis was performed using Haploview.
  
  
  RESULTS
  TFV accumulation was significantly lower in HEK293-ABCC10 cell lines than in parental HEK293 cells (35% lower; P = .02); this was reversed by cepharanthine. siRNA knockdown of ABCC10 resulted in increased accumulation of TFV in CD4(+) cells (18%; P = .04) and MDMs (25%; P = .04). Two ABCC10 SNPs (rs9349256: odds ratio [OR], 2.3; P = .02; rs2125739, OR, 2.0; P = .05) and their haplotype (OR, 2.1; P = .05) were significantly associated with KTD. rs9349256 was associated with urine phosphorus wasting (P = .02) and β2 microglobulinuria (P = .04).
  
  
  CONCLUSIONS
  TFV is a substrate for ABCC10, and genetic variability within the ABCC10 gene may influence TFV renal tubular transport and contribute to the development of KTD. These results need to be replicated in other cohorts.
authors.affiliation: National Institute for Health Research Biomedical Research Centre, Royal Liverpool Hospital, UK.
authors.forename: Sudeep P
authors.initials: SP
authors.lastname: Pushpakom
authors.forename: Neill J
authors.initials: NJ
authors.lastname: Liptrott
authors.forename: Sonia
authors.initials: S
authors.lastname: Rodríguez-Nóvoa
authors.forename: Pablo
authors.initials: P
authors.lastname: Labarga
authors.forename: Vincent
authors.initials: V
authors.lastname: Soriano
authors.forename: Marta
authors.initials: M
authors.lastname: Albalater
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hopper-Borge
authors.forename: Stefano
authors.initials: S
authors.lastname: Bonora
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Perri
authors.forename: David J
authors.initials: DJ
authors.lastname: Back
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000235:genetics; D007684:Kidney Tubules / Q000187:drug effects* / Q000502:physiology; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D063065:Organophosphonates / Q000008:administration & dosage / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide; D000068698:Tenofovir
chemical_list: D000225:Adenine; D019380:Anti-HIV Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D063065:Organophosphonates; D000068698:Tenofovir; C421142:ABCC10 protein, human