Department of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
J Allergy Clin Immunol. 2010 Aug;126(2):338-46, 346.e1-10. doi: 10.1016/j.jaci.2010.04.024.
Regulatory T-cell dysfunction is associated with development of the complex genetic conditions atopy and asthma. Therefore, we hypothesized that single nucleotide polymorphisms in genes involved in the development and function of regulatory T cells are associated with atopy and asthma development.
To evaluate main effects and gene-gene interactions of haplotype tagging single nucleotide polymorphisms of genes involved in regulatory T-cell function-IL6, IL6R, IL10, heme-oxygenase 1 (HMOX1), IL2, Toll-like receptor 2 (TLR2), TGFB1, TGF-beta receptor (TGFBR)-1, TGFBR2, IL2RA, and forkhead box protein 3 (FOXP3)-in relation to atopy and asthma.
Single-locus and multilocus associations with total IgE (3rd vs 1st tertile); specific IgE to egg, milk, and indoor allergens; and asthma were evaluated by chi(2) tests and the multifactor dimensionality-reduction method in 3 birth cohorts (Allergenic study).
Multiple statistically significant multilocus associations existed. IL2RA rs4749926 and TLR2 rs4696480 associated with IgE in both age groups tested (1-2 and 6-8 years). TGFBR2 polymorphisms associated with total and specific IgE in both age groups and with asthma. TGFBR2 rs9831477 associated with specific IgE for milk at age 1 to 2 years and indoor allergens at age 6 to 8 years. For milk-specific IgE, interaction between TGFBR2 and FOXP3 polymorphisms was confirmed by logistic regression and consistent in 2 birth cohorts and when stratified for sex, supplying internal replications.
Genes involved in the development and function of regulatory T cells, specifically IL2RA, TLR2, TGFBR2, and FOXP3, associate with atopy and asthma by gene-gene interaction. Modeling of multiple gene-gene interactions is important to unravel further the genetic susceptibility to atopy and asthma.
调节性 T 细胞功能障碍与特应性和哮喘等复杂遗传疾病的发生有关。因此，我们假设调节性 T 细胞发育和功能相关基因中的单核苷酸多态性与特应性和哮喘的发生有关。
评估调节性 T 细胞功能相关基因（IL6、IL6R、IL10、血红素加氧酶 1（HMOX1）、IL2、Toll 样受体 2（TLR2）、TGFB1、TGF-beta 受体（TGFBR）-1、TGFBR2、IL2RA 和叉头框蛋白 3（FOXP3））单核苷酸多态性的单体型标记及其基因-基因相互作用与特应性和哮喘的关系。
采用卡方检验和多因子降维法，在 3 个出生队列（过敏研究）中评估单核苷酸多态性与总 IgE（第 3 分位与第 1 分位）、特定 IgE 对卵、奶和室内过敏原的关系，以及与哮喘的关系。
存在多个统计学意义上的多基因关联。IL2RA rs4749926 和 TLR2 rs4696480 与两个年龄组（1-2 岁和 6-8 岁）的 IgE 均相关。TGFBR2 多态性与两个年龄组的总 IgE 和特异性 IgE 以及哮喘相关。TGFBR2 rs9831477 与 1-2 岁时的牛奶特异性 IgE 和 6-8 岁时的室内过敏原特异性 IgE 相关。对于牛奶特异性 IgE，TGFBR2 和 FOXP3 多态性之间的相互作用通过逻辑回归得到确认，并在 2 个出生队列中得到一致验证，并且在性别分层时也是如此，提供了内部复制。
调节性 T 细胞发育和功能相关基因（特别是 IL2RA、TLR2、TGFBR2 和 FOXP3）通过基因-基因相互作用与特应性和哮喘相关。对多个基因-基因相互作用进行建模对于进一步揭示特应性和哮喘的遗传易感性非常重要。
