title: Single-nucleotide polymorphisms in the UDP-glucuronosyltransferase 1A-3' untranslated region are associated with atazanavir-induced nephrolithiasis in patients with HIV-1 infection: a pharmacogenetic study.
abstract: OBJECTIVE
  Ritonavir-boosted atazanavir (atazanavir/ritonavir) is a widely used antiretroviral drug, though it can potentially cause nephrolithiasis. The aim of this study was to determine the relationship between polymorphisms in genes encoding proteins involved in metabolism and transportation of atazanavir, and atazanavir/ritonavir-induced nephrolithiasis in HIV-1-infected patients treated with atazanavir/ritonavir.
  
  
  METHODS
  Nineteen SNPs in the ABCB1, NR1I2, UGT1A1, SLCO1B1 and CYP3A5 genes were examined in case patients with atazanavir/ritonavir-induced nephrolithiasis (n = 31) and controls (n = 47). Case patients were those with a clinical diagnosis of nephrolithiasis while on atazanavir/ritonavir, based on new-onset acute flank pain plus one of the following: (i) new-onset haematuria; (ii) documented presence of stones by either abdominal ultrasonography or CT; or (iii) confirmed stone passage. Control patients were consecutively enrolled among those with >2 years of atazanavir/ritonavir exposure free of nephrolithiasis. Genotyping was performed by allelic discrimination using TaqMan 5'-nuclease assays with standard protocols. Associations between alleles and atazanavir/ritonavir-induced nephrolithiasis were tested by univariate and multivariate logistic regression analyses.
  
  
  RESULTS
  Multivariate analysis showed a significant association between atazanavir/ritonavir-induced nephrolithiasis and genotype T/C versus C/C at position c.211 (adjusted OR = 3.7; 95% CI, 1.13-11.9; P = 0.030), genotype G/C versus C/C at 339 (adjusted OR = 5.8; 95% CI, 1.56-21.3; P = 0.009) and genotype G/G or G/C versus C/C at 440 (adjusted OR = 5.8; 95% CI, 1.56-21.3; P = 0.009) of the UGT1A-3' untranslated region (UTR).
  
  
  CONCLUSIONS
  This is the first known study to identify the association between SNPs in the UGT1A-3'-UTR and atazanavir-induced nephrolithiasis. Further studies are warranted to confirm this association and to elucidate how these SNPs might influence atazanavir exposure.
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nishijima
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Kiyoto
authors.initials: K
authors.lastname: Tsuchiya
authors.affiliation: Biostatistics Section, Department of Clinical Research and Informatics, Clinical Science Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Akane
authors.initials: A
authors.lastname: Joya
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Hamada
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Mizushima
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Aoki
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Ei
authors.initials: E
authors.lastname: Kinai
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Haruhito
authors.initials: H
authors.lastname: Honda
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Yazaki
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Tanuma
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Kunihisa
authors.initials: K
authors.lastname: Tsukada
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Katsuji
authors.initials: K
authors.lastname: Teruya
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Kikuchi
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oka
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan Center for AIDS Research, Kumamoto University, Kumamoto, Japan higatana@acc.ncgm.go.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Gatanaga
mesh_terms: D020413:3' Untranslated Regions; D000293:Adolescent; D000328:Adult; D000368:Aged; D000069446:Atazanavir Sulfate; D016022:Case-Control Studies; D005260:Female; D005838:Genotype; D060005:Genotyping Techniques; D014453:Glucuronosyltransferase / Q000235:genetics*; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008875:Middle Aged; D053040:Nephrolithiasis / Q000139:chemically induced*; D009842:Oligopeptides / Q000009:adverse effects* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011725:Pyridines / Q000009:adverse effects* / Q000627:therapeutic use; D055815:Young Adult; D000099148:UGT1A1 Enzyme
chemical_list: D020413:3' Untranslated Regions; D000069446:Atazanavir Sulfate; D014453:Glucuronosyltransferase; D009842:Oligopeptides; D011725:Pyridines; D000099148:UGT1A1 Enzyme
keywords: SNPs; atazanavir sulphate; renal stones