A Single-Nucleotide Polymorphism in ABCC4 Is Associated with Tenofovir-Related Beta2-Microglobulinuria in Thai Patients with HIV-1 Infection

PLoS One. 2016 Jan 25;11(1):e0147724. doi: 10.1371/journal.pone.0147724. eCollection 2016.

Abstract

Background: In Thailand, the combined generic anti-retroviral drug stavudine/lamivudine/nevirapine (d4T/3TC/NVP) has been used to treat human immunodeficiency virus (HIV)-infected individuals since 2001. Due to relatively frequent adverse effects, d4T gradually has been replaced with tenofovir disoproxil fumarate (TDF). Although the frequency of adverse drug effects with TDF is lower than that with d4T, TDF is known to induce kidney dysfunction, especially in the proximal tubules. It has been reported that renal tubular transporters, including members of the multi-drug resistant (MDR) protein family, are implicated in tenofovir extrusion and may, therefore, confer susceptibility to TDF-induced kidney tubular dysfunction (KTD). We have explored the association between KTD and polymorphisms in genes that encode adenosine triphosphate-binding cassette (ABC)-type MDRs.

Methods: HIV-infected patients receiving TDF-containing antiretroviral regimens for at least one year were enrolled in the study. The levels of beta2-microglobulin in urine and creatinine (Cr) were measured. Three single-nucleotide polymorphisms, ABCC2 C-24T (rs717620), ABCC2 G1429A (rs2273697), and ABCC4 T4976C (rs1059751), were analyzed using TaqMan SNP genotyping assays.

Results: A total of 273 HIV-infected patients were recruited. The median number of years of TDF treatment was 5.04 with interquartile range (IQR) of 3.9-6.7. Despite the length of treatment with TDF, 98.5% patients maintained an estimated glomerular filtration rate (eGFR) of >60 mL/min as calculated by the CKD-EPI formula. Fifty-four patients (19.8%) showed beta2-microglobulinuria (median 2636 μg/g Cr with IQR of 1519-13197 μg/g Cr). The allele frequency of ABCC4 T4976C among those 54 patients was 0.602, compared to 0.475 among the 219 remaining patients (p = 0.018).

Conclusions: Approximately 20% of HIV-infected patients receiving TDF showed beta2-microglobulinuria. The C allele at position 4976 of the ABCC4 gene was associated with beta2-microglobulinuria in this population. This polymorphism may help to identify patients at greater risk for developing TDF-associated KTD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antiretroviral Therapy, Highly Active / adverse effects*
  • Female
  • Gene Frequency
  • Gene-Environment Interaction
  • Genotype
  • HIV Infections / drug therapy
  • HIV Infections / genetics*
  • Humans
  • Kidney Diseases / chemically induced*
  • Kidney Diseases / genetics*
  • Lamivudine / adverse effects
  • Lamivudine / therapeutic use
  • Male
  • Middle Aged
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins / genetics*
  • Nevirapine / adverse effects
  • Nevirapine / therapeutic use
  • Polymorphism, Single Nucleotide*
  • Stavudine / adverse effects
  • Stavudine / therapeutic use
  • Tenofovir / adverse effects*
  • Tenofovir / therapeutic use
  • Thailand

Substances

  • ABCC2 protein, human
  • ABCC4 protein, human
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins
  • stavudine, lamivudine, nevirapine drug combination
  • Lamivudine
  • Nevirapine
  • Tenofovir
  • Stavudine

Grants and funding

This work was supported by the grant from the Ministry of Health, Labor, and Welfare in Japan, the Ministry of Education, Culture, Sports, Science, and Technology, Japan; the Japan Initiative for Global Research Network on Infectious Diseases, directed by the Ministry of Education, Culture, Sports, Science, and Technology of Japan and Bamrasnaradura Infectious Diseases Institute, Department of Disease Control, Ministry of Public Health, Nonthaburi, Thailand. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.