Corydon Thomas Juhl, Haagerup Annette, Jensen Thomas Gryesten, Binderup Helle Glud, Petersen Mikkel Steen, Kaltoft Keld, Vestbo Jørgen, Kruse Torben Arvid, Børglum Anders Dupont
Institute of Human Genetics, the Bartholin Building, University of Aarhus, DK-8000 Aarhus C, Denmark.
J Med Genet. 2007 Aug;44(8):509-15. doi: 10.1136/jmg.2007.049536. Epub 2007 May 18.
Several studies have documented a substantial genetic component in the aetiology of allergic diseases and a number of atopy susceptibility loci have been suggested. One of these loci is 3q21, at which linkage to multiple atopy phenotypes has been reported. This region harbours the CD86 gene encoding the costimulatory B7.2 protein. The costimulatory system, consisting of receptor proteins, cytokines and associated factors, activates T cells and regulates the immune response upon allergen challenge.
We sequenced the CD86 gene in patients with atopy from 10 families that showed evidence of linkage to 3q21. Identified polymorphisms were analysed in a subsequent family-based association study of two independent Danish samples, respectively comprising 135 and 100 trios of children with atopy and their parents. Functional analysis of the costimulatory effect on cytokine production was performed in an autologous cell-based system based on cells expressing CD86 variants.
Two polymorphisms were identified, encoding the amino acid changes Ile179Val and Ala304Thr, respectively. Significant associations were observed between the Ile179Val polymorphism and allergy phenotypes in both samples (eg, asthma, p = 4 x 10(-3) in the two samples combined). The undertransmitted (protective) Val179 allele was found to induce higher production of both Th1 and Th2 cytokines than the overtransmitted (risk) Ile179 allele, suggesting a functional impact of the polymorphism.
The CD86 gene, and specifically the Ile179Val polymorphism, may be a novel aetiological factor in the development of asthma and related allergic disorders.
多项研究证实变应性疾病的病因中存在重要的遗传成分，并提出了一些特应性易感基因座。其中一个基因座是3q21，已有报道该区域与多种特应性表型存在连锁关系。该区域包含编码共刺激分子B7.2蛋白的CD86基因。由受体蛋白、细胞因子及相关因子组成的共刺激系统可激活T细胞，并在变应原激发时调节免疫反应。
我们对来自10个与3q21有连锁证据的特应性患者家系的CD86基因进行了测序。在随后一项基于家系的关联研究中，分别对两个独立的丹麦样本中的已识别多态性进行了分析，这两个样本分别包含135个和100个患有特应性的儿童及其父母组成的三联体。在基于表达CD86变体的细胞的自体细胞系统中，对细胞因子产生的共刺激作用进行了功能分析。
识别出两个多态性，分别编码氨基酸变化Ile179Val和Ala304Thr。在两个样本中均观察到Ile179Val多态性与过敏表型之间存在显著关联（例如，哮喘，两个样本合并时p = 4×10⁻³）。发现传递不足（保护性）的Val179等位基因比传递过多（风险）的Ile179等位基因诱导产生更高水平的Th1和Th2细胞因子，提示该多态性具有功能影响。
CD86基因，特别是Ile179Val多态性，可能是哮喘及相关变应性疾病发生发展中的一个新的病因学因素。
