title: Polymorphism in glutamate cysteine ligase catalytic subunit (GCLC) is associated with sulfamethoxazole-induced hypersensitivity in HIV/AIDS patients.
abstract: BACKGROUND
  Sulfamethoxazole (SMX) is a commonly used antibiotic for prevention of infectious diseases associated with HIV/AIDS and immune-compromised states. SMX-induced hypersensitivity is an idiosyncratic cutaneous drug reaction with genetic components. Here, we tested association of candidate genes involved in SMX bioactivation and antioxidant defense with SMX-induced hypersensitivity.
  
  
  RESULTS
  Seventy seven single nucleotide polymorphisms (SNPs) from 14 candidate genes were genotyped and assessed for association with SMX-induced hypersensitivity, in a cohort of 171 HIV/AIDS patients. SNP rs761142 T > G, in glutamate cysteine ligase catalytic subunit (GCLC), was significantly associated with SMX-induced hypersensitivity, with an adjusted p value of 0.045. This result was replicated in a second cohort of 249 patients (p = 0.025). In the combined cohort, heterozygous and homozygous carriers of the minor G allele were at increased risk of developing hypersensitivity (GT vs TT, odds ratio = 2.2, 95% CL 1.4-3.7, p = 0.0014; GG vs TT, odds ratio = 3.3, 95% CL 1.6 - 6.8, p = 0.0010). Each minor allele copy increased risk of developing hypersensitivity 1.9 fold (95% CL 1.4 - 2.6, p = 0.00012). Moreover, in 91 human livers and 84 B-lymphocytes samples, SNP rs761142 homozygous G allele carriers expressed significantly less GCLC mRNA than homozygous TT carriers (p < 0.05).
  
  
  CONCLUSIONS
  rs761142 in GCLC was found to be associated with reduced GCLC mRNA expression and with SMX-induced hypersensitivity in HIV/AIDS patients. Catalyzing a critical step in glutathione biosynthesis, GCLC may play a broad role in idiosyncratic drug reactions.
authors: Department of Pharmacology, Program in Pharmacogenomics, School of Biomedical Science, College of Medicine, Ohio State University, Columbus, OH 43210, USA. wang.808@osu.edu
authors: Danxin
authors: D
authors: Wang
authors: Amanda
authors: A
authors: Curtis
authors: Audrey C
authors: AC
authors: Papp
authors: Susan L
authors: SL
authors: Koletar
authors: Michael F
authors: MF
authors: Para
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy; D000328:Adult; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D020134:Catalytic Domain; D005260:Female; D060005:Genotyping Techniques; D005721:Glutamate-Cysteine Ligase / Q000737:chemistry / Q000235:genetics*; D005978:Glutathione / Q000096:biosynthesis / Q000378:metabolism; D015658:HIV Infections / Q000150:complications*; D006801:Humans; D006967:Hypersensitivity / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D008658:Inactivation, Metabolic; D008297:Male; D020641:Polymorphism, Single Nucleotide; D013420:Sulfamethoxazole / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D013420:Sulfamethoxazole