Munthe-Kaas Monica Cheng, Carlsen Kai Håkon, Helms Peter J, Gerritsen Jorrit, Whyte Moira, Feijen Marlies, Skinningsrud Beate, Main Margaret, Kwong Georges Ng Man, Lie Benedicte A, Lødrup Carlsen Karin C, Undlien Dag E
Department of Pediatrics,Ullevål University Hospital, University of Oslo, Norway.
J Allergy Clin Immunol. 2004 Aug;114(2):280-7. doi: 10.1016/j.jaci.2004.03.050.
Several genomic regions are reported to be associated with the development of asthma and allergy, including chromosome 2q33. This region harbors the candidate gene cytotoxic T-lymphocyte antigen 4 (CTLA-4), an important regulator of T-cell activation and differentiation.
We sought to explore possible associations between CTLA-4 polymorphisms and allergy and asthma.
Seven single nucleotide polymorphisms (SNPs; MH30, -1147CT, +49AG, CT60, JO31, JO30, JO27_1) in CTLA-4 were analyzed for associations with total serum IgE, allergic sensitization (positive skin prick test to common allergens), bronchial hyperresponsiveness (BHR) to methacholine, asthma, and lung function (FEV1 % of predicted) in 364 asthmatic families from 3 European countries.
Transmission disequilibrium test analysis showed that several SNPs were significantly associated with serum IgE levels, allergy, asthma, and FEV1 % predicted below 80%, but not with BHR, and CTLA-4 polymorphisms of potentially direct pathogenic significance in atopic disorders were identified.
We identified associations between 4 newly discovered SNPs in the CTLA-4 gene and serum IgE levels, allergy, asthma, and reduced lung function, but not BHR, suggesting an important role for CTLA-4 in atopy and reduced lung function in asthmatic subjects rather than asthma per se. The particular SNP alleles found positively associated with our phenotypes were recently shown to be associated negatively with autoimmune disorders. Although a skewing toward a TH1 reactivity pattern is believed to characterize autoimmune diseases, atopic diseases are considered TH2-mediated. Hence, our data suggest a role for CTLA-4 polymorphisms in determining the TH1/TH2 balance and identify CTLA-4 signaling as a potential therapeutic target in atopic disease.
据报道，包括2q33染色体在内的几个基因组区域与哮喘和过敏的发生有关。该区域包含候选基因细胞毒性T淋巴细胞抗原4（CTLA-4），它是T细胞活化和分化的重要调节因子。
我们试图探究CTLA-4基因多态性与过敏和哮喘之间的可能关联。
对来自3个欧洲国家的364个哮喘家庭中的CTLA-4基因的7个单核苷酸多态性（SNP；MH30、-1147C/T、+49A/G、CT60、JO31、JO30、JO27_1）进行分析，以确定其与总血清IgE、过敏致敏（对常见变应原皮肤点刺试验阳性）、对乙酰甲胆碱的支气管高反应性（BHR）、哮喘以及肺功能（预测FEV1%）之间的关联。
传递不平衡检验分析表明，几个SNP与血清IgE水平、过敏、哮喘以及预测FEV1%低于80%显著相关，但与BHR无关，并且确定了CTLA-4基因多态性在特应性疾病中具有潜在的直接致病意义。
我们发现CTLA-4基因中的4个新发现的SNP与血清IgE水平、过敏、哮喘以及肺功能降低有关，但与BHR无关，这表明CTLA-4在哮喘患者的特应性和肺功能降低中起重要作用，而非哮喘本身。最近发现与我们的表型呈正相关的特定SNP等位基因与自身免疫性疾病呈负相关。尽管人们认为向TH1反应模式倾斜是自身免疫性疾病的特征，但特应性疾病被认为是由TH2介导的。因此，我们的数据表明CTLA-4基因多态性在决定TH1/TH2平衡中起作用，并确定CTLA-4信号传导是特应性疾病的潜在治疗靶点。
