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. 2011 Jul 1;204(1):145-53.
doi: 10.1093/infdis/jir215.

Genetic variants of ABCC10, a novel tenofovir transporter, are associated with kidney tubular dysfunction

Sudeep P Pushpakom  1 , Neill J Liptrott, Sonia Rodríguez-Nóvoa, Pablo Labarga, Vincent Soriano, Marta Albalater, Elizabeth Hopper-Borge, Stefano Bonora, Giovanni Di Perri, David J Back, Saye Khoo, Munir Pirmohamed, Andrew Owen
Affiliations

Genetic variants of ABCC10, a novel tenofovir transporter, are associated with kidney tubular dysfunction

Sudeep P Pushpakom et al. J Infect Dis. .

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.

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Figures

Figure 1.
Figure 1.
Graphic representation of ABCC10 gene and single-nucleotide polymorphism (SNP) markers selected. Exons are represented by gray boxes. Approximate locations of SNP markers are shown. Haplotype tag SNPs are shown in bold italic type.
Figure 2.
Figure 2.
Accumulation of radiolabeled TFV in ABCC10-expressing cell lines. ABCC10-overexpressing cells C17 and C18 showed a significant reduction in the intracellular accumulation of tenofovir (TFV), suggesting ABCC10-mediated TFV efflux. Cepharanthine (2 μmol), a potent ABCC10 inhibitor, prevents this efflux. Data expressed as means ± standard deviations (n = 6).
Figure 3.
Figure 3.
Knockdown of ABCC10 in CD4+ T cells and monocyte-derived macrophages (MDMs) and accumulation of tenofovir (TFV) 48 h after knockdown. A–D, Expression of ABCC10 messenger RNA in CD4+ cells (A) and MDMs (B ) and of ABCC10 protein in CD4+ cells (C ) and MDMs (D ), after small interfering RNA (siRNA)–mediated knockdown. GAPDH, glyceraldehyde 3-phosphate dehydrogenase. E, F, Accumulation of TFV is increased after knockdown in CD4+ cells (E ) and MDMs (F ). Data are expressed as means ± standard deviations (n = 6). *p<0.05; **p<0.01; ***p<0.01
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