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

• Published in: PloS one Vol. 11; no. 1; p. e0147724
• Main Authors: Likanonsakul, Sirirat, Suntisuklappon, Bussakorn, Nitiyanontakij, Ravee, Prasithsirikul, Wisit, Nakayama, Emi E, Shioda, Tatsuo, Sangsajja, Chariya
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.01.2016; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; Adenosine; Adenosine triphosphate; Adult; AIDS; Albuminuria; Alleles; Analysis; Antiretroviral agents; Antiretroviral drugs; Antiretroviral Therapy, Highly Active - adverse effects; ATP; Biology and Life Sciences; Complications and side effects; Creatinine; Deoxyribonucleic acid; DNA; Dosage and administration; Drug resistance; Drug therapy; Epidermal growth factor receptors; Extrusion; Female; Gene Frequency; Gene polymorphism; Gene-Environment Interaction; Genes; Genetic aspects; Genetic testing; Genotype; Genotyping; Glomerular filtration rate; Health aspects; HIV; HIV infections; HIV Infections - drug therapy; HIV Infections - genetics; Human immunodeficiency virus; Humans; Infections; Infectious diseases; Kidney Diseases - chemically induced; Kidney Diseases - genetics; Lamivudine; Lamivudine - adverse effects; Lamivudine - therapeutic use; Male; Medicine and Health Sciences; Middle Aged; Multidrug resistance; Multidrug Resistance-Associated Proteins - genetics; Nevirapine; Nevirapine - adverse effects; Nevirapine - therapeutic use; Patients; Physical Sciences; Physiological aspects; Polymorphism; Polymorphism, Single Nucleotide; Proteins; Proximal tubules; Risk factors; Side effects; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Stavudine; Stavudine - adverse effects; Stavudine - therapeutic use; Tenofovir; Tenofovir - adverse effects; Tenofovir - therapeutic use; Thailand; Urine; Viruses; β2 Microglobulin; Thailand; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0147724

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. 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. 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). 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.