IRAK-M is involved in the pathogenesis of early-onset persistent asthma
IRAK-M is involved in the pathogenesis of early-onset persistent asthma
复制标题
DOI：
10.1086/518259
复制
发表时间：
2007-06-01
影响因子：
9.8
通讯作者：
Pilia, Giuseppe
中科院分区：
文献类型：
--
作者：
Balaci, Lenuta;Spada, Maria Cristina;Pilia, Giuseppe
哮喘是一种受遗传和环境因素影响的多因素疾病。在过去的十年中，至少在一个人群中发现了几个位点和1100个基因与这种疾病有关。在这些基因座中，12q13-24区域与多个人群的哮喘病因有关，表明它含有一个或多个哮喘易感基因。我们在候选区域12q13-24进行了连锁和关联分析，通过传播/不平衡检验和病例对照分析，使用撒丁岛创始人人群，其中单基因和复杂疾病的致病等位基因以及环境条件的有限异质性应有助于多因子性状的研究。我们分析了我们的队列，在哮喘发作时使用13岁的截止年龄，并检测到与12q13-24部分的显著关联。我们确定IRAK-M是促成这种联系的基因，并表明它与早发性持续性哮喘有关。我们定义了保护性和易感性SNP单倍型，并在意大利近交人群中复制了相关关系。对患者的序列分析发现IRAK-M编码区发生突变，包括失活病变。肺活检免疫组化结果显示，IRAK-M在上皮细胞中高表达。我们报道IRAK-M参与早发性持续性哮喘的发病机制。IRAK-M是toll样受体/IL-1R通路的负调节因子，是nf - κ B和炎症的主要调节因子。我们的数据表明先天免疫系统的过度激活与慢性气道炎症之间存在机制联系，并表明IRAK-M是哮喘治疗干预的潜在靶点。
Asthma is a multifactorial disease influenced by genetic and environmental factors. In the past decade, several loci and 1100 genes have been found to be associated with the disease in at least one population. Among these loci, region 12q13-24 has been implicated in asthma etiology in multiple populations, suggesting that it harbors one or more asthma susceptibility genes. We performed linkage and association analyses by transmission/ disequilibrium test and case-control analysis in the candidate region 12q13-24, using the Sardinian founder population, in which limited heterogeneity of pathogenetic alleles for monogenic and complex disorders as well as of environmental conditions should facilitate the study of multifactorial traits. We analyzed our cohort, using a cutoff age of 13 years at asthma onset, and detected significant linkage to a portion of 12q13-24. We identified IRAK-M as the gene contributing to the linkage and showed that it is associated with early-onset persistent asthma. We defined protective and predisposing SNP haplotypes and replicated associations in an outbred Italian population. Sequence analysis in patients found mutations, including inactivating lesions, in the IRAK-M coding region. Immunohistochemistry of lung biopsies showed that IRAK-M is highly expressed in epithelial cells. We report that IRAK-M is involved in the pathogenesis of early-onset persistent asthma. IRAK-M, a negative regulator of the Toll-like receptor/IL-1R pathways, is a master regulator of NF-kappa B and inflammation. Our data suggest a mechanistic link between hyperactivation of the innate immune system and chronic airway inflammation and indicate IRAK-M as a potential target for therapeutic intervention against asthma.