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Logo of bmcmedgenoBioMed Centralsearchsubmit a manuscriptregisterthis articleBMC Medical Genomics
 
BMC Med Genomics. 2012; 5: 32.
Published online Jul 23, 2012. doi:  10.1186/1755-8794-5-32
PMCID: PMC3418550
Polymorphism in glutamate cysteine ligase catalytic subunit (GCLC) is associated with sulfamethoxazole-induced hypersensitivity in HIV/AIDS patients
Danxin Wang,corresponding author1 Amanda Curtis,1 Audrey C Papp,1 Susan L Koletar,2 and Michael F Para2
1Department of Pharmacology, Program in Pharmacogenomics, School of Biomedical Science, College of Medicine, Ohio State University, Columbus, OH, 43210, USA
2Division of Infectious Diseases, Internal Medicine, College of Medicine, Ohio State University, Columbus, OH, 43210, USA
corresponding authorCorresponding author.
Danxin Wang: wang.808/at/osu.edu; Amanda Curtis: Curtis.164/at/osu.edu; Audrey C Papp: papp.2/at/osu.edu; Susan L Koletar: Koletar.1/at/osu.edu; Michael F Para: para.1/at/osu.edu
Received May 14, 2012; Accepted July 23, 2012.
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.
Keywords: Idiosyncratic drug reaction, Sulfamethoxazole, Hypersensitivity, Glutamate cysteine ligase catalytic subunit (GCLC), Association, HIV/AIDS
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