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Open Access Research article

Polymorphism in glutamate cysteine ligase catalytic subunit (GCLC) is associated with sulfamethoxazole-induced hypersensitivity in HIV/AIDS patients

Danxin Wang1*, Amanda Curtis1, Audrey C Papp1, Susan L Koletar2 and Michael F Para2

Author Affiliations

1 Department of Pharmacology, Program in Pharmacogenomics, School of Biomedical Science, College of Medicine, Ohio State University, Columbus, OH, 43210, USA

2 Division of Infectious Diseases, Internal Medicine, College of Medicine, Ohio State University, Columbus, OH, 43210, USA

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BMC Medical Genomics 2012, 5:32  doi:10.1186/1755-8794-5-32

Published: 23 July 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