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

Abstract

BackgroundSulfamethoxazole (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.ResultsSeventy 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).Conclusionsrs761142 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.

Analysis of genes polymorphism of catecholamines metabolism and antioxidant system in women with recurrent miscarriage

“…Синтез глутатиона происходит под воздействием фермента глутаматцистеинлигазы (GCL), состоящей из двух субъединиц -регуляторной субъединицы (GCLM) и обеспечивающей каталитическую актив-ность фермента (GCLC) [19]. В настоящем исследовании мы провели изуче-ние полиморфизма С129Т (rs 17883901) гена GCLC, при котором происходит замена цитозина на тимин в позиции 129.…”

Pharmacogenomics of Antimicrobial Agents

“…A study of 14 candidate genes in HIV-infected patients with SMX hypersensitivity (102 cases vs 318 controls) also found significant association with SNP rs76114 2T>G in GCLC (adjusted p = 0.045) [73]. Heterozygous (TG) and homozygous (GG) are at increased risk compared with TT genotype (OR: 2.2 and 3.3, respectively).…”

The role of gene polymorphisms of glutamate-cysteine ligase catalytic (GCLC) enzyme against antioxidants and oxidative stress status of Individual who had contacted infectious tuberculosis

“…Polymorphismresulted GCL enzyme expression and activity are significantly reduced. Moreover, phenotype indicates the severity of the disease, such as myocardial infarction, cancer, diabetes and HIV / AIDS (Koide et al, 2003;Wang et al, 2012). The GCL gene polymorphism and the level of glutathione and F2-isoprostanes in the TB patients and normal individuals have been describe (Nwanjo and Oze, 2007;Yuniastuti et al, 2013), but for the contacts of person with infectious TB have never been reported.…”