The IL1RN Promoter rs4251961 Correlates with IL-1 Receptor Antagonist Concentrations in Human Infection and Is Differentially Regulated by GATA-1
The IL1RN Promoter rs4251961 Correlates with IL-1 Receptor Antagonist Concentrations in Human Infection and Is Differentially Regulated by GATA-1
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DOI：
10.4049/jimmunol.1002402
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发表时间：
2011-02-15
影响因子：
4.4
通讯作者：
Ollier, William E.
中科院分区：
文献类型：
--
作者：
Carrol, Enitan D.;Payton, Antony;Ollier, William E.
IL-1 R拮抗剂（IL-1 Ra）是侵袭性肺炎球菌病（IPD）中充分的宿主防御所必需的。IL 1 RN基因（C/T）启动子多态性（rs 4251961）的次要等位基因已被证明与健康成人中IL-1 Ra产生减少相关。我们对299名IPD患儿进行了基因分型，并检测了19个IL 1 RN单倍型标记单核苷酸多态性。用含有等位基因变体C（pGL 3 pCC）或T（pGL 3 pTT）的启动子报告质粒pGL 3 p转染人胚肾HEK 293（T）细胞，与过表达球蛋白转录因子加塔-1的表达构建体共转染或不共转染。死亡者血浆IL-1 Ra浓度显著高于存活者（p < 0.0005），并且rs 4251961的C等位基因与IPD急性期血浆IL-1 Ra浓度显著升高相关（p = 0.01）。这些结果在276例未经治疗的HIV感染成人队列中得到验证，具有临界显著性（p = 0.058）。功能分析表明，与基础活性相比，含有T等位基因的启动子构建体的活性增加了约6倍，在加塔-1存在下，含有C等位基因的启动子构建体的活性增加了约9倍（p < 0.001）。我们的研究结果表明，IL-1 Ra单核苷酸多态性rs 4251961在IPD和其他人类感染的病理生理学中起着关键作用。免疫学杂志，2011，186：2329-2335。
IL-1R antagonist (IL-1Ra) is required for adequate host defense in invasive pneumococcal disease (IPD). The minor allele of an IL1RN gene (C/T) promoter polymorphism (rs4251961) has been shown to be associated with decreased IL-1Ra production in healthy adults. We genotyped 299 children with IPD, and examined 19 IL1RN haplotype-tagging single-nucleotide polymorphisms. Human embryonic kidney HEK293(T) cells were transfected with the promoter reporter plasmid pGL3p containing either allelic variant C (pGL3pCC) or T (pGL3pTT) with or without cotransfection with an expression construct overexpressing the globin transcription factor GATA-1. Plasma IL-1Ra concentrations were significantly higher in nonsurvivors compared with survivors (p < 0.0005), and the C allele of rs4251961 was associated with a significant increase in plasma IL-1Ra concentrations (p = 0.01) during the acute illness of IPD. These findings were validated in a cohort of 276 treatment-naive HIV-infected adults, with borderline significance (p = 0.058). Functional analyses demonstrated that the activity of the promoter constructs containing the T allele increased similar to 6-fold as compared with basal activity, and that containing the C allele by similar to 9-fold (p < 0.001) in the presence of GATA-1. Our findings suggest that the IL-1Ra single-nucleotide polymorphism rs4251961 plays a key role in the pathophysiology of IPD and in other human infections. The Journal of Immunology, 2011, 186: 2329-2335.