Functional impact of IL33 polymorphisms on asthma & other Th2-mediated diseases

IL33 多态性对哮喘的功能影响

• 批准号: 8622214
• 负责人: Kathleen C Barnes
• 金额: $ 72.67万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-15 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8622214
• 关键词: African; African American; Allergic Disease; American; Antibodies; Antigens; Asthma; Binding; Biological; Biological Assay; Biological Process; Biology; Brazil; Candidate Disease Gene; Characteristics; Childhood; Complex; DNA; DNA Resequencing; Data; Development; Disease; Ethnic group; European; Family; Gene Proteins; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Goals; Haplotypes; Hispanics; Human; Hygiene; IgE; IgG4; Immunity; Individual; Infection; Institution; Interleukin-1; Interleukin-1 Receptors; Interleukin-5; Interleukins; International; Life; Linkage Disequilibrium; Lung; Mass Spectrum Analysis; Measures; Mediating; Membrane; Meta-Analysis; Methods; Mexico; Modeling; Mucous Membrane; Mus; Myeloid Cells; National Heart, Lung, and Blood Institute; Outcome; Parasites; Pathogenesis; Pathway interactions; Population Heterogeneity; Predisposition; Production; Proteins; Proteomics; Public Health; Reaction; Recording of previous events; Research; Research Personnel; Resistance; Risk; Role; Sampling; Schistosoma; Schistosoma mansoni; Schistosomiasis; Serum; Signal Transduction; Source; Testing; Trichuris; Variant; airway inflammation; base; case control; cohort; cytokine; environmental allergen; epidemiology study; genetic association; genetic epidemiology; genetic variant; genome wide association study; genome-wide linkage; insight; interdisciplinary approach; mast cell; member; monocyte; mouse model; multidisciplinary; multiple reaction monitoring; novel; promoter; protein expression; pyroglyphid; rare variant; receptor; response; risk variant; trait; translational study

DESCRIPTION (provided by applicant): Asthma is a complex trait with an established genetic basis that represents a major public health burden. The usual source of the lower airway inflammation characteristic of asthma is a Th2-mediated reaction initiated by common environmental allergens which involves the production of antigen-specific IgE antibodies. An inverse relationship between allergic disease and helminthic infection, also characterized by elevated IgE, has long been observed, and individuals with a history of asthma appear to be 'protected' from helminthic parasites (i.e., Schistosoma mansoni). Many genes have been associated with asthma, but to date very few have replicated. Recently, three independent genome-wide association studies (GWAS) representing over 40,000 DNA samples have identified significant associations between polymorphisms in and flanking the Interleukin-33 (IL33) gene and asthma, rendering IL33 as one of the strongest candidate genes for asthma to date. We observed significant associations between the same IL33 'asthma risk' variants and outcomes associated with schistosomiasis in villagers living in an endemic region in Bahia, Brazil. IL-33 is a new member of the IL-1 family that induces Th2 cytokines. Its receptor, interleukin 1-like (or ST2) exists as membrane and circulating soluble proteins, and ST2 polymorphisms were also associated with asthma in one of the asthma GWAS's. The mechanism(s) by which IL-33 skews the Th2 response at the level of the mucosa, leading to asthma and immunity to parasites, is not known. Our ongoing genetic epidemiology studies in large cohorts characterized for risk of asthma and resistance to schistosomiasis provide a unique opportunity to test the hypothesis that IL33 polymorphisms contribute to both diseases by altering the function of IL-33. To accomplish our goals, we have amassed a multidisciplinary team of investigators from 6 institutions to: (i) quantify circulating IL-33 and its receptor, sST2, in serum from 500 asthma cases and controls using a mass spectrometry (MS)- based method called 'multiple reaction monitoring' (MRM) that provides absolute quantification of protein, and to test for association between IL-33 and sST2 concentrations and IL33 genotypes/haplotypes; (ii) characterize the effects of IL33 genetic variation on production of IL-33 and sST2, in response to Th2-promoting antigens (dust mite, schistosome) in human myeloid cells; (iii) test for co-associations between the IL33 variants/haplotypes that skew the Th2 response in asthma and a quantitative outcome representing resistance (S. mansoni antigen-specific IgE:IgG4 ratio) to schistosomiasis and serum levels of IL-33 and ST2 in samples from 500 villagers living in a region endemic for schistosomiasis in Bahia, Brazil; and (iv) develop a humanized murine model of IL33 haplotypes associated with risk/resistance to asthma/schistosomiasis to elucidate the functional role of the IL33 gene in these diseases. Results from this study will provide novel insights into the role of IL-33 in the pathogenesis of two diseases of high public health significance.

描述（由申请人提供）：哮喘是一种具有既定遗传基础的复杂特征，是一种主要的公共卫生负担。哮喘下气道炎症特征的通常来源是由常见环境过敏原引发的th2介导的反应，涉及抗原特异性IgE抗体的产生。长期以来，人们一直观察到过敏性疾病与蠕虫感染（同样以IgE升高为特征）之间存在反比关系，有哮喘史的个体似乎可以“保护”免受蠕虫寄生虫（即曼氏血吸虫）的侵害。许多基因与哮喘有关，但迄今为止很少有基因能够复制。最近，三个独立的全基因组关联研究（GWAS）代表了超过40,000个DNA样本，已经确定了白细胞介素-33 （IL33）基因的多态性和侧翼与哮喘之间的显著关联，使IL33成为迄今为止最强的哮喘候选基因之一。在巴西巴伊亚流行地区的村民中，我们观察到相同的IL33“哮喘风险”变异与血吸虫病相关结果之间存在显著关联。IL-33是IL-1家族的新成员，可诱导Th2细胞因子。其受体白介素1样（interleukin 1-like，或ST2）以膜和循环可溶性蛋白的形式存在，ST2多态性也与其中一种哮喘GWAS的哮喘有关。IL-33在粘膜水平上扭曲Th2反应，导致哮喘和寄生虫免疫的机制尚不清楚。我们正在进行的以哮喘风险和血吸虫病抗性为特征的大型队列遗传流行病学研究提供了一个独特的机会来检验IL-33多态性通过改变IL-33的功能导致这两种疾病的假设。为了实现我们的目标，我们聚集了来自6个机构的多学科研究团队：(i)使用基于质谱（MS）的“多反应监测”（MRM）方法定量500例哮喘患者和对照组血清中的循环IL-33及其受体sST2，该方法提供了蛋白质的绝对定量，并测试IL-33和sST2浓度与IL-33基因型/单倍型之间的关系；（ii）表征IL-33遗传变异对IL-33和sST2产生的影响，以响应人髓细胞中促进th2的抗原（尘螨、血吸虫）；（iii）在巴西巴伊亚州血吸虫病流行地区的500名村民样本中，检测导致哮喘患者Th2反应的IL-33变异/单倍型与代表血吸虫病耐药性（曼氏链球菌抗原特异性IgE:IgG4比率）的定量结果和血清IL-33和ST2水平之间的共同关联；（iv）建立与哮喘/血吸虫病风险/抗性相关的IL33单倍型人源化小鼠模型，以阐明IL33基因在这些疾病中的功能作用。这项研究的结果将为IL-33在两种具有高度公共卫生意义的疾病的发病机制中的作用提供新的见解。