CISH and susceptibility to infectious diseases.
CISH and susceptibility to infectious diseases.
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DOI：
10.1056/nejmoa0905606
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发表时间：
2010-06-03
期刊：
影响因子：
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通讯作者：
Hill AV
中科院分区：
文献类型：
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作者：
Khor CC;Vannberg FO;Chapman SJ;Guo H;Wong SH;Walley AJ;Vukcevic D;Rautanen A;Mills TC;Chang KC;Kam KM;Crampin AC;Ngwira B;Leung CC;Tam CM;Chan CY;Sung JJ;Yew WW;Toh KY;Tay SK;Kwiatkowski D;Lienhardt C;Hien TT;Day NP;Peshu N;Marsh K;Maitland K;Scott JA;Williams TN;Berkley JA;Floyd S;Tang NL;Fine PE;Goh DL;Hill AV
白细胞介素-2 （IL2）介导的免疫反应对宿主防御传染性病原体至关重要。CISH是细胞因子信号传导的抑制因子，控制il - 2信号传导。我们使用病例对照设计对来自冈比亚、香港、肯尼亚、马拉维和越南的8402人进行了CISH多态性与主要传染病（菌血症、结核病和严重疟疾）易感性之间的关联测试。我们之前已经在一个或多个样本收集中测试了20个其他免疫相关基因。我们观察到，在每个研究人群中，多种CISH多态性的变异等位基因与每种传染病的易感性增加之间存在关联。当将CISH相关位点内的所有五个snp （CISH - 639、- 292、- 163、+1320和+3415）一起纳入多snp评分时，我们发现CISH遗传变异对菌血症、疟疾和结核病易感性的影响（总体P=3.8 ×10 - 11）得到了大量支持，其中CISH- 292“负责”大部分关联信号（P=4.58×10 - 7）。与缺乏- 292变体的“对照”细胞相比，携带CISH - 292变体的成年志愿者外周血单个核细胞对IL2刺激的反应较弱，CISH减少25-40%。CISH的变异与对多种感染性病原体引起的疾病的易感性有关，这表明细胞因子信号的负调节因子可能在对各种感染性疾病的免疫中发挥重要作用。研究发现，携带变异CISH等位基因的个体患这些传染病的总风险至少增加了18%。
The interleukin-2 (IL2)-mediated immune response is critical for host defence against infectious pathogens. CISH, a suppressor of cytokine signalling, controls IL2 signalling. We tested for association between CISH polymorphisms and susceptibility to major infectious diseases (bacteremia, tuberculosis and severe malaria) in 8402 persons from the Gambia, Hong Kong, Kenya, Malawi, and Vietnam using a case-control design. We have previously tested twenty other immune-related genes in one or more of these sample collections. We observed associations between variant alleles of multiple CISH polymorphisms and increased susceptibility to each infectious disease in each of the study populations. When all five SNPs (CISH −639, −292, −163, +1320 and +3415) within the CISH-associated locus were considered together in a multi-SNP score, we found substantial support for an effect of CISH genetic variants on susceptibility to bacteremia, malaria, and tuberculosis (overall P=3.8 × 10−11) with CISH −292 being “responsible” for the majority of the association signal (P=4.58×10−7). Peripheral blood mononuclear cells of adult volunteers carrying the CISH −292 variant showed a muted response to IL2 stimulation — in the form of 25-40% less CISH — when compared with “control” cells lacking the −292 variant. Variants of CISH are associated with susceptibility to diseases caused by diverse infectious pathogens, suggesting that negative regulators of cytokine signalling may play a major role in immunity against various infectious diseases. The overall risk of having one of these infectious diseases was found to be increased by at least 18 percent in individuals carrying the variant CISH alleles.