ASTHMA

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者的研究机构。 在美国，哮喘影响超过1400万人。1从1980年到1996年，美国哮喘的患病率增加了74.9%; 1在这种哮喘发病率增加的趋势中，少数民族人群（如波多黎各人）的比例不成比例。2，3从1990年到1995年，波多黎各人在美国西班牙裔中，特别是在美国东北部的西班牙裔中，年龄调整后的哮喘死亡率最高。 虽然哮喘是波多黎各人的一个主要公共卫生问题，但人们对遗传和环境因素对这一人群哮喘的影响知之甚少。5迄今为止，13个不同人群中的11个小组已经发表了与哮喘表型相关的全基因组分析结果。6-17这些基因组扫描都不包括波多黎各人。由于在美国大陆的波多黎各人中单亲家庭的患病率很高，因此很难在这一人群中进行以家庭为基础的遗传关联研究。在美国大陆的波多黎各人中进行一项以人群为基础的哮喘和哮喘相关表型遗传相关性的病例对照研究是可行的，并将提供一个独特的机会来研究哮喘发病率高的少数人群中的遗传和环境危险因素。我们招募了哈特福德的哮喘儿童（康涅狄格州）作为改善该社区医生哮喘管理计划的一部分。19在这些儿童中，我们已经表明波多黎各种族与对特定过敏原的敏感性和哮喘严重程度增加有关。20，21在哈特福德的学童中，我们收集了一组患有哮喘的波多黎各儿童（病例）和一组没有哮喘的波多黎各儿童（对照）的数据。我们建议进行一项病例对照研究，选择遗传和环境因素与波多黎各人哮喘之间的关联。75%至94%的波多黎各儿童哮喘是特应性的（见C.4.c）.22在特应性儿童中，辅助性T（Th）2细胞的IL-4、IL-5、IL-9和IL-13促进免疫球蛋白E（IgE）的产生增加、嗜酸性粒细胞增多、肥大细胞分化和变应原特异性免疫的长期表达。24特应性和特应性哮喘可能是由于Th 1免疫应答缺乏上调和/或Th 2免疫应答下调不足所致。25，26我们假设，控制Th 1细胞、Th 2细胞、和调节性T细胞（T细胞）与波多黎各儿童的哮喘和/或哮喘的中间表型（哮喘表型）有关。我们进一步假设，父母报告的接触宠物在早期的生活，（在怀孕期间和/或生命的第一年）与哮喘和特应性的风险降低有关，并且目前暴露于高水平的室内过敏原与a）哮喘严重程度增加和肺功能表型异常有关（FEV 1和FEV 1/FVC降低，气道反应性增加，支气管扩张剂反应性降低）和B）特应性表型（例如，增加血清总IgE）在波多黎各儿童哮喘和非哮喘。此外，我们假设控制Th 1细胞、Th 2细胞和Tcl 3的发育和调节的基因变异与室内过敏原暴露相互作用，影响波多黎各儿童的哮喘和哮喘严重程度。 为了验证这些假设，我们将追求以下具体目标：1。招募500名波多黎各哮喘儿童（病例）和500名波多黎各非哮喘儿童（对照组）。 2.检测20个位置候选基因中的单核苷酸多态性（SNP）与i）哮喘之间的关联（在所有受试者中），ii）肺功能表型（气道反应性、FEV 1、FEV 1/FVC和支气管扩张剂反应）和特应性表型（皮肤试验对过敏原的反应性、血清总IgE和过敏原特异性IgE以及嗜酸性粒细胞计数），和iii）病例中的哮喘严重程度。3a.检查i）父母是否报告曾接触宠物（狗和/或猫）在生命早期与哮喘风险降低有关（所有受试者）和特应性（分别在病例和对照受试者中），和B）当前暴露于室内过敏原（尘螨、蟑螂、狗、猫、小鼠和大鼠）与哮喘严重程度增加和肺功能表型异常有关，并分别在病例和对照受试者中具有特应性表型。3b.研究暴露于特定目标3a中概述的室内过敏原与特定目标2中选择的候选基因中的SNP之间的相互作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Asthma affects over 14 million people in the United States.1 The prevalence of asthma in the U.S. increased by 74.9% from 1980 to 1996; 1 ethnic minority populations such as Puerto Ricans are disproportionately represented in this trend of increasing asthma morbidity. 2, 3 Puerto Ricans had the highest age-adjusted asthma mortality from 1990 to 1995 among U.S. Hispanics in general and among Hispanics in the U.S. Northeast in particular. Although asthma is a major public health problem among Puerto Ricans, little is known about the contribution of genetic and environmental factors to asthma in this population. 5 To date, results of genome-wide analyses for linkage to asthma phenotypes have been published by 11 groups in 13 distinct populations. 6-17 None of these genome scans included Puerto Ricans. Because of the high prevalence of single-parent households among Puerto Ricans in the U.S. mainland,18 family-based studies of genetic association would be difficult to perform in this population. A population-based case-control study of genetic association for asthma and asthma-related phenotypes among Puerto Ricans in the U.S mainland is feasible and would offer a unique opportunity to examine genetic and environmental risk factors in a minority population with high asthma morbidity. We have recruited children with asthma in Hartford (Connecticut) as part of a program to improve asthma management by physicians in this community.19 In these children, we have shown that Puerto Rican ethnicity is associated with sensitization to specific allergens and increased asthma severity.20, 21 Among school children in Hartford, we have collected data in a group of Puerto Rican children with asthma (cases) and a group of Puerto Rican children without asthma (controls). We propose to conduct a case-control study of association between selected genetic and environmental factors and asthma in Puerto Ricans. Between 75% and 94% of Puerto Rican children with asthma are atopic (see C.4.c).22 In atopic children, production of cytokines (IL-4, IL-5, IL-9, and IL-13) by T-helper (Th)2 cells promotes increased production of immunoglobulin E (IgE), eosinophilia, mast cell differentiation, and long-term expression of allergen-specific immunity.23,24 Atopy and atopic asthma may result from lack of upregulation of Th1 immune responses and/or inadequate downregulation of Th2 immune responses.25, 26 We hypothesize that single nucleotide polymorphisms (SNPs) in genes that control the development and regulation of Th1 cells, Th2 cells, and regulatory T cells (Tregs) are associated with asthma and/or intermediate phenotypes of asthma (asthma phenotypes") in Puerto Rican children. We further hypothesize that parental report of exposure to pets in early life (during pregnancy and/or the first year of life) is associated with reduced risks of asthma and atopy, and that current exposure to high levels of indoor allergens is associated with a) increased asthma severity and abnormal lung function phenotypes (reduced FEV1 and FEV1/FVC, increased airway responsiveness, and reduced bronchodilator responsiveness) in Puerto Rican children with asthma and b) atopy phenotypes (e.g., increased serum total IgE) in Puerto Rican children with and without asthma. In addition, we hypothesize that variants in genes that control the development and regulation of Th1 cells, Th2 cells, and Tregs interact with indoor allergen exposures in influencing asthma and asthma severity in Puerto Rican children. To test these hypotheses, we will pursue the following specific aims: 1. To recruit 500 Puerto Rican children with asthma (cases) and 500 Puerto Rican children without asthma (control subjects). 2. To test for association between Single Nucleotide Polymorphisms (SNPs) in 20 positional candidate genes and i) asthma (in all subjects), ii) lung function phenotypes (airway responsiveness, FEV1, FEV1/FVC, and bronchodilator response)and atopy phenotypes (skin test reactivity to allergens, serum total and allergen-specific IgE, and eosinophil count) separately in cases and in control subjects, and iii) asthma severity in cases. 3a. To examine whether i) parental report of exposure to pets (dogs and/or cats) in early life is associated with reduced risks of asthma (in all subjects) and atopy (separately in cases and in control subjects), and b) current exposure to indoor allergens (dust mite, cockroach, dog, cat, mouse, and rat) is associated with increased asthma severity and abnormal lung function phenotypes in cases, and with atopy phenotypes separately in cases and in control subjects. 3b. To examine interactions between exposure to the indoor allergens outlined in Specific Aim 3a and SNPs in the candidate genes selected in Specific Aim 2.