Christensen Ulla, Haagerup Annette, Binderup Helle G, Vestbo Jørgen, Kruse Torben A, Børglum Anders D
Institute of Human Genetics, The Bartholin Building, University of Aarhus, Aarhus C, Denmark.
Eur J Hum Genet. 2006 Feb;14(2):227-35. doi: 10.1038/sj.ejhg.5201541.
Allergic diseases affect an increasing number of individuals and are a major global health problem. A substantial genetic contribution in the aetiology of allergic diseases is well documented. We have previously reported linkage of allergic diseases and atopy to the region harbouring the IL2 gene (4q27). IL15 is located approximately 20 Mb distal to IL2. The two genes encode cytokines that are structurally and functionally related, both inducing T-cell activation and proliferation. We screened the two genes for sequence variation and applied the seven single-nucleotide polymorphisms (SNPs) identified in a family based association study of two Danish samples comprising a total of 235 families with allergic diseases. None of the IL15 SNPs showed significant association and the haplotype analysis yielded inconsistent results in the two samples. In contrast, the two IL2 SNPs showed association both separately and in haplotypes with several atopic phenotypes, most significantly with IgE-mediated allergy. (single SNP P-value 0.0005 for positive skin prick test, haplotype P-value 0.019 for positive RAST test). To our knowledge, this is the first study reporting association between IL2 and IgE-mediated allergy, asthma and atopic eczema. The SNP (rs2069762) that showed the most consistent results is located in the promoter and has previously been shown to influence the level of IL2 expression. We suggest that the observed overtransmission of the T allele of this SNP may convey increased susceptibility to allergic disease by skewing the Th1/Th2 balance towards Th2.
过敏性疾病影响着越来越多的人，是一个重大的全球健康问题。过敏性疾病病因学中存在显著的遗传因素，这一点已有充分记载。我们之前报道过过敏性疾病和特应性与包含IL2基因（4q27）的区域存在连锁关系。IL15位于IL2下游约20 Mb处。这两个基因编码结构和功能相关的细胞因子，均可诱导T细胞活化和增殖。我们筛查了这两个基因的序列变异，并将在一项基于家系的关联研究中鉴定出的7个单核苷酸多态性（SNP）应用于两个丹麦样本，这两个样本共有235个患有过敏性疾病的家系。IL15的SNP均未显示出显著关联，单倍型分析在两个样本中得出了不一致的结果。相比之下，两个IL2的SNP无论是单独还是以单倍型形式都与几种特应性表型相关联，与IgE介导的过敏最为显著相关（阳性皮肤点刺试验的单个SNP P值为0.0005，阳性放射性变应原吸附试验的单倍型P值为0.019）。据我们所知，这是第一项报道IL2与IgE介导的过敏、哮喘和特应性皮炎之间存在关联的研究。显示出最一致结果的SNP（rs2069762）位于启动子区域，此前已证明其会影响IL2的表达水平。我们认为，该SNP的T等位基因观察到的过度传递可能通过使Th1/Th2平衡偏向Th2而增加对过敏性疾病的易感性。
