title: Impact of GSTM1, GSTT1 and GSTP1 gene polymorphism and risk of ARV-associated hepatotoxicity in HIV-infected individuals and its modulation.
abstract: Glutathione S-transferase (GST) family is involved in a two-stage detoxification process of a wide range of environmental toxins, carcinogen and antiretroviral (ARV) therapy (ART) drugs. The aim of this study is to describe the impact of genetic polymorphisms of GSTM1, GSTT1 and GSTP1-313A/G in the risk of ARV-associated hepatotoxicity in HIV-infected individuals and its modulation in hepatotoxic patients. We enrolled a total of 34 patients with hepatotoxicity, 131 HIV-infected individuals without hepatotoxicity under non-nucleoside reverse transcriptase inhibitor containing ART and 153 unrelated healthy individuals. With a case-control design, polymorphisms of GSTM1, GSTT1 and GSTP1-313A/G gene were genotyped by PCR and restriction enzyme-length polymorphism. Genotypes of GSTT1 null were significantly higher in HIV-infected individuals as compared with healthy controls (P=0.01, odds ratio (OR)=1.54). HIV-infected individuals with GSTM1-null genotype showed higher risk (P=0.09, OR=1.37) for hepatotoxicity, but risk was not significant. On evaluating gene-gene interaction models, GSTM1 null and GSTT1 null showed significant association with the risk of hepatotoxicity in HIV-infected individuals (P=0.004, OR=2.67) owing to synergistic effect of these genes. Individuals with GSTT1-null and GSTM1-null genotypes showed higher risk of hepatotoxicity with advanced stage of (CD4<200) of HIV infection (P=0.18, OR=1.39; P=0.63, OR=1.13). In case-only analysis, GSTT1-null genotype among alcohol users showed elevated risk of hepatotoxicity in HIV-infected individuals (P=0.12, OR=1.36, 95% confidence interval (CI): 0.94-1.97) as compared with GSTT1 genotypes. The carriers GSTM1-null+GSTT1-null genotype among nevirapine user showed prominent risk of hepatotoxicity in HIV-infected individuals (P=0.12, OR=4.21, 95% CI: 0.60-29.54). Hence, we can conclude that GSTT1-null and GSTM1-null genotypes alone and in combination may predict the acquisition of hepatotoxicity.
authors.affiliation: Department of Molecular Biology, National AIDS Research Institute, Pune, India.
authors.forename: H O
authors.initials: HO
authors.lastname: Singh
authors.affiliation: Department of Molecular Biology, National AIDS Research Institute, Pune, India.
authors.forename: S
authors.initials: S
authors.lastname: Lata
authors.affiliation: Department of Clinical Sciences, National AIDS Research Institute, Pune, India.
authors.forename: M
authors.initials: M
authors.lastname: Angadi
authors.affiliation: Department of Clinical Sciences, National AIDS Research Institute, Pune, India.
authors.forename: S
authors.initials: S
authors.lastname: Bapat
authors.affiliation: Department of Clinical Sciences, National AIDS Research Institute, Pune, India.
authors.forename: J
authors.initials: J
authors.lastname: Pawar
authors.affiliation: Department of Molecular Biology, National AIDS Research Institute, Pune, India.
authors.forename: V
authors.initials: V
authors.lastname: Nema
authors.affiliation: Department of Clinical Sciences, National AIDS Research Institute, Pune, India.
authors.forename: M V
authors.initials: MV
authors.lastname: Ghate
authors.affiliation: Department of Clinical Sciences, National AIDS Research Institute, Pune, India.
authors.forename: S
authors.initials: S
authors.lastname: Sahay
authors.affiliation: Department of Clinical Sciences, National AIDS Research Institute, Pune, India.
authors.forename: R R
authors.initials: RR
authors.lastname: Gangakhedkar
mesh_terms: D000328:Adult; D000428:Alcohol Drinking / Q000009:adverse effects; D019380:Anti-HIV Agents / Q000009:adverse effects*; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000235:genetics*; D016009:Chi-Square Distribution; D004843:Epistasis, Genetic; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D005982:Glutathione Transferase / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007194:India; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D000071185:Pharmacogenomic Testing; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D019380:Anti-HIV Agents; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C413545:glutathione S-transferase T1; C496556:GSTP1 protein, human