Association of IL12B promoter polymorphism with severity of atopic and non-atopic asthma in children
Association of IL12B promoter polymorphism with severity of atopic and non-atopic asthma in children
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DOI：
10.1016/s0140-6736(02)09676-9
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发表时间：
2002-08-10
期刊：
影响因子：
168.9
通讯作者：
Holt, PG
中科院分区：
文献类型：
--
作者：
Morahan, G;Huang, DX;Holt, PG
背景 严重哮喘是入院的常见原因，尤其是儿童。哮喘气道炎症的主要环境诱因是病毒和空气过敏原。这些药物会引发相互免疫反应，其特征是分别产生辅助性 T 细胞因子 1 和辅助性 T 细胞因子 2。对于哮喘患者如何对这些不同的环境刺激产生过度反应，目前还没有遗传学解释。我们的目的是评估 IL12B 启动子多态性与哮喘之间的关系。方法我们进行了一项队列研究，首先对 411 名 6 岁儿童进行了 IL12B 启动子多态性基因分型。然后我们评估了这种多态性与哮喘严重程度之间的关系：然后对来自同一队列的 433 名儿童的额外样本中的另外 85 名哮喘儿童进行了评估，以证实这些发现。我们还检查了一个亚组个体的体外白细胞介素 12 反应。结果在初始样本中 76% (16) 患有严重哮喘的特应性和非特应性个体中观察到 IL12B 启动子多态性杂合性。相比之下，中度哮喘组中杂合子仅占 31% (17)，轻度哮喘组中 48% (20) 是杂合子，未受影响的对照组也是如此。这些发现在第二个样本中得到了证实（总体 p < 0.0001）。我们的数据表明，IL12B 启动子杂合性会导致哮喘严重程度，而不是易感性本身。严重倾向基因型与白细胞介素 12 p40 基因转录减少和白细胞介素 12 p70 分泌减少相关。解释 白细胞介素 12 在拮抗 T 辅助细胞 2 分化和诱导抗病毒宿主防御中发挥关键作用。因此，基因决定的白细胞介素 12 反应能力的减弱将为两种主要类型的哮喘的疾病严重程度提供一条看似合理的共同免疫学途径。
Background Severe asthma is a frequent cause of hospital admission, especially among children. The main environmental triggers of airway inflammation in asthma are viruses and aeroallergens. These agents elicit reciprocal immune responses, characterised by production of T helper 1 and T helper 2 cytokines, respectively. There is no genetic explanation for how hyper-responsiveness to these disparate environmental stimuli develops among individuals with asthma. Our aim was to assess relation between an IL12B promoter polymorphism and asthma.Methods We did a cohort study in which we initially genotyped 411 6-year olds for the IL12B promoter polymorphism. We then assessed the relation between this polymorphism and asthma severity: A further 85 asthmatic children in an additional sample of 433 children from the same cohort were then assessed to confirm these findings. We also examined in-vitro interleukin-12 responses in a subgroup of individuals.Findings Heterozygosity for the IL12B promoter polymorphism was observed in 76% (16) of atopic and non-atopic individuals with severe asthma in the initial sample. By comparison, heterozygotes comprised only 31% (17) of the moderate asthma group, and 48% (20) of individuals with mild asthma were heterozygous, as were unaffected controls. These findings were confirmed in the second sample (overall p < 0.0001). Our data suggest that IL12B promoter heterozygosity contributes to asthma severity rather than susceptibility per se. The severity-predisposing genotype was associated with reduced interleukin 12 p40 gene transcription and decreased interleukin 12 p70 secretion.Interpretation Interleukin 12 plays a key part in antagonism of T helper 2 differentiation, and in induction of antiviral host defense. Genetically determined attenuation of interleukin-12 response capacity would, therefore, provide a plausible common immunological pathway to disease severity for the two major forms of asthma.