Polymorphism in glutamate cysteine ligase catalytic subunit (GCLC) is associated with sulfamethoxazole-induced hypersensitivity in HIV/AIDS patients.
Polymorphism in glutamate cysteine ligase catalytic subunit (GCLC) is associated with sulfamethoxazole-induced hypersensitivity in HIV/AIDS patients.
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DOI：
10.1186/1755-8794-5-32
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发表时间：
2012-07-23
影响因子：
2.7
通讯作者：
Para MF
中科院分区：
文献类型：
--
作者：
Wang D;Curtis A;Papp AC;Koletar SL;Para MF
磺胺甲恶唑（SMX）是一种常用的抗生素，用于预防与艾滋病毒/艾滋病和免疫受损状态相关的传染病。SMX诱导的超敏反应是具有遗传成分的特异质皮肤药物反应。在这里，我们测试了参与SMX生物激活和抗氧化防御的候选基因与SMX诱导的超敏反应的关联。来自14个候选基因的77个单核苷酸多态性（SNPs）进行了基因分型，并评估了与SMX诱导的超敏反应的相关性，在171例HIV/AIDS患者的队列中。谷氨酸半胱氨酸连接酶催化亚基（GCLC）中的SNP rs761142 T > G与SMX诱导的超敏反应显著相关，校正p值为0.045。这一结果在第二个队列的249例患者中重复（p = 0.025）。在联合队列中，次要G等位基因的杂合子和纯合子携带者发生超敏反应的风险增加（GT vs TT，比值比= 2.2，95% CL 1.4-3.7，p = 0.0014; GG vs TT，比值比= 3.3，95% CL 1.6 - 6.8，p = 0.0010）。每个次要等位基因拷贝使发生超敏反应的风险增加1.9倍（95% CL 1.4 - 2.6，p = 0.00012）。此外，在91个人类肝脏和84个B淋巴细胞样品中，SNP rs761142纯合G等位基因携带者表达的GCLC mRNA显著低于纯合TT携带者（p < 0.05）。发现GCLC中的rs761142与HIV/AIDS患者中GCLC mRNA表达降低和SMX诱导的超敏反应相关。催化谷胱甘肽生物合成的关键步骤，GCLC可能在特异质药物反应中发挥广泛作用。
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. 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). 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.
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影响因子：
3.8
作者：
Littera, Roberto;Carcassi, Carlo;Manconi, Paolo Emilio
通讯作者：
Manconi, Paolo Emilio
DOI：
10.1073/pnas.0409500102
发表时间：
2005-03-15
影响因子：
11.1
作者：
Hung, SL;Chung, WH;Chen, YT
通讯作者：
Chen, YT
影响因子：
13.5
作者：
Lucena, M. Isabel;Garcia-Martin, Elena;Agundez, Jose A. G.
通讯作者：
Agundez, Jose A. G.
DOI：
10.1097/00008571-199902000-00007
发表时间：
1999-02-01
期刊：
PHARMACOGENETICS
影响因子：
--
作者：
Gill, HJ;Tjia, JF;Park, BK
通讯作者：
Park, BK
影响因子：
3.2
作者：
Hosomi, Hiroko;Akai, Sho;Yokoi, Tsuyoshi
通讯作者：
Yokoi, Tsuyoshi