Genetic & Environmental Risk Factors in Asthma Severity

遗传

• 批准号: 6518218
• 负责人: Brian P Leaderer
• 金额: $ 43.41万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-09 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6518218
• 关键词: adrenergic receptor; air pollution; airborne allergen; asthma; blood chemistry; child (0-11); disease /disorder etiology; disease /disorder proneness /risk; gene environment interaction; gene expression; gene interaction; genetic polymorphism; genetic promoter element; human subject; immunoglobulin E; interleukin 4; patient oriented research; racial /ethnic difference; respiratory function

Over the past two decades asthma morbidity among children has increased dramatically, with disproportionate morbidity among Hispanic and African-Americans. Environmental factors (allergens, fungi, environmental tobacco smoke, air contaminants, cold air, etc.) are known to be associated with asthma severity in children. More recently genetic factors have been proposed as important determinants in the severity of asthma. The interaction of specific mutations within genes with specific environmental factors, however, is poorly understood despite its crucial importance in understanding asthma severity. In this application we seek to expand our asthma severity study to examine the gene-environment interactions in modifying asthma severity. The asthmatic children (14 percent Black, 27 percent Hispanic, 55 percent, Caucasian, 4 percent Other and 16 percent of mothers with an education level of less than 12 years of schooling) are currently being followed to test the hypothesis that carefully quantified indoor allergen exposures (house dust mite, cat, dog, cockroach and fungi) and air contaminant exposures (environmental tobacco smoke, nitrogen dioxide, nitrous acid, ozone, fine particle mass and pollen) are associated with asthma severity (daily respiratory symptoms, medication use, and utilization of health care services and lung function) in a population of 1,002 physician diagnosed asthmatic children between 5 and 12 years of age whose health status familial history, home environment, and potential confounders are carefully characterized. In this application we will investigate the respective roles of allergens, ETS and other air contaminant exposures and the presence of polymorphisms in the beta2 adrenergic receptor (Arg 16-Gly or Gln27-Glu) and in the promoter region of the IL-4 gene, particularly the TT polymorphism, in asthma severity while controlling for allergic status of the child. Although several candidate genes have been identified as potential genetic determinants of asthma severity, we chose beta2-AR and IL-4 polymorphisms as the initial genes to examine in this population because they have been linked to asthma severity. By collecting and storing blood samples, other candidate genes could be examined, as they are prioritized. Our extensive characterization of environmental exposures and risk factors for a large diverse population of asthmatic children, provide a unique population within which gene-environment interactions in the severity of asthma can be examined. This study will provide a basis to prioritizing environmental interventions to reduce asthma morbidity in children.

在过去的二十年里，儿童哮喘发病率急剧增加，其中西班牙裔和非裔美国人的发病率不成比例。环境因素(过敏原、真菌、环境烟草烟雾、空气污染物、冷空气等)已知与儿童哮喘的严重程度有关。最近，遗传因素被认为是哮喘严重程度的重要决定因素。然而，尽管基因内特定突变与特定环境因素的相互作用在了解哮喘严重性方面至关重要，但人们对此知之甚少。在这项应用中，我们试图扩展我们的哮喘严重性研究，以检查基因-环境相互作用在改变哮喘严重性方面的作用。目前正在跟踪哮喘儿童(14%是黑人，27%是西班牙裔，55%是高加索人，4%是其他人，16%是受教育程度低于12年的母亲)，以检验这样一个假设，即仔细量化室内过敏原暴露(屋尘螨、猫、狗、蟑螂和真菌)和空气污染物暴露(环境烟草烟雾、二氧化氮、亚硝酸、臭氧、细颗粒物和花粉)与哮喘严重程度(日常呼吸道症状、药物使用、卫生保健服务和肺功能的利用)有关的人口中，1002名医生诊断为哮喘儿童的5至12岁的健康状况，家庭环境和潜在的混杂因素被仔细地描述。在这项应用中，我们将研究过敏原、ETS和其他空气污染物暴露以及β2肾上腺素能受体(Arg 16-Gly或Gln27-Glu)和IL-4基因启动子区存在的多态，特别是TT多态在哮喘严重程度中的作用，同时控制儿童的过敏状态。尽管几个候选基因已被确定为哮喘严重程度的潜在遗传决定因素，但我们选择β2-AR和IL-4多态作为在该人群中进行研究的初始基因，因为它们与哮喘严重程度有关。通过采集和存储血液样本，可以检查其他候选基因，因为它们是优先的。我们对大量不同哮喘儿童的环境暴露和风险因素进行了广泛的表征，提供了一个独特的人群，在这个人群中可以研究哮喘严重程度中的基因-环境交互作用。这项研究将为优先进行环境干预以减少儿童哮喘发病率提供依据。