title: A Single-Nucleotide Polymorphism in ABCC4 Is Associated with Tenofovir-Related Beta2-Microglobulinuria in Thai Patients with HIV-1 Infection.
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.
authors.affiliation: Bamrasnaradura Infectious Diseases Institute, Department of Disease Control, Ministry of Public Health, Nonthaburi, Thailand.
authors.forename: Sirirat
authors.initials: S
authors.lastname: Likanonsakul
authors.affiliation: Bamrasnaradura Infectious Diseases Institute, Department of Disease Control, Ministry of Public Health, Nonthaburi, Thailand.
authors.forename: Bussakorn
authors.initials: B
authors.lastname: Suntisuklappon
authors.affiliation: Bamrasnaradura Infectious Diseases Institute, Department of Disease Control, Ministry of Public Health, Nonthaburi, Thailand.
authors.forename: Ravee
authors.initials: R
authors.lastname: Nitiyanontakij
authors.affiliation: Bamrasnaradura Infectious Diseases Institute, Department of Disease Control, Ministry of Public Health, Nonthaburi, Thailand.
authors.forename: Wisit
authors.initials: W
authors.lastname: Prasithsirikul
authors.affiliation: Department of Viral Infections, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Emi E
authors.initials: EE
authors.lastname: Nakayama
authors.affiliation: Department of Viral Infections, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Shioda
authors.affiliation: Bamrasnaradura Infectious Diseases Institute, Department of Disease Control, Ministry of Public Health, Nonthaburi, Thailand.
authors.forename: Chariya
authors.initials: C
authors.lastname: Sangsajja
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D005260:Female; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced* / Q000235:genetics*; D019259:Lamivudine / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D019829:Nevirapine / Q000009:adverse effects / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D018119:Stavudine / Q000009:adverse effects / Q000627:therapeutic use; D000068698:Tenofovir / Q000009:adverse effects* / Q000627:therapeutic use; D013785:Thailand
chemical_list: D019259:Lamivudine; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019829:Nevirapine; D018119:Stavudine; D000068698:Tenofovir; C000715087:ABCC2 protein, human; C073492:ABCC4 protein, human; C516355:stavudine, lamivudine, nevirapine drug combination