哮喘联盟

   摘要
   背景：表观遗传标记是受环境影响的可遗传的标记。它们调控T淋巴细胞的成熟，且在小鼠能促进过敏性气道疾病的发展。因此确定哮喘人群中表观遗传的改变非常重要。
   目的：我们假设循环PBMCs的表观遗传改变与过敏性哮喘相关。
   方法：我们通过提取PBMCs的DNA和RNA，比较了市中心儿童患有持续性过敏性哮喘者和健康对照者PBMCs中的DNA甲基化方式和基因表达情况。结果在一个独立的哮喘患者样本中得到验证。
   结果：通过对哮喘患者(n= 97)和对照者(n= 97)进行比较，我们共发现81个不同的甲基化位点。在哮喘患者中，低甲基化的有多个免疫基因，包括IL13，RUNX3及与T淋巴细胞（TIGIT）相关的特异性基因。在哮喘患者，11个不同的甲基化位点与血清高IgE含量相关，16个与FEV1预计值的百分比相关。低甲基化和高甲基化分别与基因表达升高和降低相关（哮喘P < 6 × 10-12，IgE P< .01）。我们采用综合分析进一步探讨了DNA甲基化和基因表达之间的关系，并发现了其他与哮喘相关的候补基因（IL4和ST2）。在一个独立的市中心哮喘儿童样本中验证了T细胞成熟(RUNX3）、TH2免疫(IL4)及氧化应激（过氧化氢酶）中有甲基化标记。
   结论：我们的结果表明特定基因位点的甲基化修饰与哮喘相关，提示表观遗传改变可能在与哮喘相关的免疫表型建立方面发挥重要作用。
 

（杨冬 审校）
JAllergyClinImmunol. 2015Mar11.pii:S0091-6749(15)00115-3.doi:10.1016/j.jaci.2015.01.025. [Epub ahead of print]
 

DNA methylation and childhood asthma in the inner city.
 

Yang IV1, Pedersen BS2, Liu A3, O'Connor GT4, Teach SJ5, Kattan M6, Misiak RT7,Gruchalla R8, Steinbach SF4, Szefler SJ9, Gill MA8, Calatroni A10, David G10, Hennessy CE2, Davidson EJ2, Zhang W11, Gergen P12, Togias A12, Busse WW13, Schwartz DA14.
 

ABSTRACT
BACKGROUND:Epigenetic marks are heritable, influenced by the environment, direct the maturation of T lymphocytes, and in mice enhance the development of allergic airway disease. Thus it is important to define epigenetic alterations in asthmatic populations.
OBJECTIVE:We hypothesize that epigenetic alterations in circulating PBMCs are associated with allergic asthma.
METHODS:We compared DNA methylation patterns and gene expression in inner-city children with persistent atopic asthma versus healthy control subjects by using DNA and RNA from PBMCs. Results were validated in an independent population of asthmatic patients.
RESULTS:Comparing asthmatic patients (n = 97) with control subjects (n = 97), we identified 81 regions that were differentially methylated. Several immune genes were hypomethylated in asthma, including IL13, RUNX3, and specific genes relevant to T lymphocytes (TIGIT). Among asthmatic patients, 11 differentially methylated regions were associated with higher serum IgE concentrations, and 16 were associated with percent predicted FEV1. Hypomethylated and hypermethylated regions were associated with increased and decreased gene expression, respectively (P < 6 × 10-12 for asthma and P < .01 for IgE). We further explored the relationship between DNA methylation and gene expression using an integrative analysis and identified additional candidates relevant to asthma (IL4 and ST2). Methylation marks involved in T-cell maturation (RUNX3), TH2 immunity (IL4), and oxidative stress (catalase) were validated in an independent asthmatic cohort of children living in the inner city.
CONCLUSIONS:Our results demonstrate that DNA methylation marks in specific gene loci are associated with asthma and suggest that epigenetic changes might play a role in establishing the immune phenotype associated with asthma.
 

JAllergyClinImmunol. 2015Mar11.pii:S0091-6749(15)00115-3.doi:10.1016/j.jaci.2015.01.025. [Epub ahead of print]