Genetic And Environmental Factors In Childhood Respirato

长期以来，人们都知道哮喘会在家庭中遗传。最近，已经进行了连锁研究，以确定涉及的特定基因。然而，这项工作进展缓慢，正在确定多个联系区域。很明显，基因-环境相互作用在决定谁患哮喘方面很重要。迄今为止进行的连锁研究尚未设计用于适当探索相互作用。鉴于哮喘的复杂性，很明显，候选基因关联研究将是必要的，以确定疾病基因和与环境因素的相互作用。 空气污染在哮喘急性发作中的作用早已被认识到。臭氧是一种氧化剂空气污染物，是可能使现有哮喘恶化的因素之一。最近的数据表明，臭氧和其他空气污染物可能在哮喘病因中发挥作用，但数据很少。最近在动物中进行的连锁研究开始确定参与对臭氧和其他吸入污染物的特定生理反应的基因。 该项目包括几项研究，研究遗传多态性、环境因素及其相互作用在儿童呼吸道疾病病因学中的作用。主要项目是在墨西哥城高度臭氧暴露人群中进行哮喘遗传易感性的家庭研究。本研究采用病例-亲本三联设计。我们正在对这些样本进行基因分析。 我与两个出生队列建立了合作关系，研究哮喘病因学中的早期生活因素。在ALSPAC研究出生队列中，我们正在研究母乳喂养与特应性和哮喘客观指标之间的关系。我还与挪威和其他欧洲哮喘研究人员合作，在挪威母亲和儿童队列（称为MoBa）中建立一个哮喘研究计划，这是一个基于人口的队列，由挪威10万名孕妇组成，一直跟踪到他们的孩子成年。哮喘项目将围绕基因-环境相互作用展开。NIEHS/MOBA部分支持MoBa研究，目的是实现此类附加研究。作为开发该项目的背景，我正在分析队列数据，以跟踪文献中已确立的发现，即出生顺序较晚的儿童患哮喘的风险较低。根据所谓的"卫生假说"，这是由于晚出生的儿童感染率较高。然而，在子宫内的环境也可能是不同的晚出生的孩子比他们的哥哥姐姐。由于MoBa是为数不多的研究之一，其中包括参加了一次以上怀孕的女性，我正在研究与后代哮喘风险相关的暴露是否从一次怀孕到下一次怀孕发生变化，以及母亲的特应性状态是否在怀孕期间发生变化。我与之建立合作的另一个队列是ALSPAC，这是一个来自英国雅芳的12,000名女性的出生队列。我们正在使用这些表型的客观测量来研究母乳喂养与哮喘和特应性的后期发展之间的关系。

Asthma has long been known to run in families. More recently, linkage studies have been conducted to identify specific genes involved. However, this work has gone slowly with multiple regions of linkage being identified. It is clear that gene-environment interactions are important in determining who develops asthma. Linkage studies conducted to date have not been designed to properly explore interactions. Given the complex nature of asthma, it is clear that candidate gene association studies will be necessary to identify disease genes and interactions with environmental factors. The role of air pollution in asthma exacerbation has long been appreciated. Ozone, an oxidant air pollutant, is one of the agents that can worsen existing asthma. Recent data suggest that ozone and other air pollutants may play a role in asthma etiology, but there are few data. Recent linkage studies in animals are beginning to identify genes that are involved in specific physiologic responses to ozone and other inhaled pollutants. This project includes several studies the role of genetic polymorphisms, environmental factors and their interaction in the etiology of childhood respiratory disease. The primary project is a family study of genetic susceptibility to asthma in a highly ozone exposed population, Mexico City. This study uses the case-parent triad design. We are actively conducting genetic analyses with these samples. I have established collaborations with two birth cohorts to study early life factors in the etiology of asthma. In the ALSPAC study birth cohort, we are examining the relation between breastfeeding and objective measures of atopy and asthma. I am also working Norwegian and other European asthma researchers to establish an asthma research program within the Norway Mother and Child Cohort (called MoBa), a population based cohort of 100,000 pregnant women in Norway who are being followed until their children reach adulthood. The asthma program will be focused around gene-environment interaction. NIEHS/DIR partially supports the MoBa study with the goal of enabling such add-on studies. As background for developing this project, I am analyzing data from the cohort to follow-up well established findings from the literature that children of later birth order are at decreased risk for asthma. This has been ascribed to greater childhood infections in later born children under the so-called "hygiene hypothesis". However, the in utero environment may also be different for later born children than for their older siblings. Because MoBa is one of the few studies including women who have enrolled for more than one pregnancy, I am examining whether exposures relevant to asthma risk in the offspring change from one pregnancy to the next and whether the atopic status of the mother changes across pregnancies. The other cohort that I have established collaboration with is ALSPAC, a birth cohort of 12,000 women in Avon, UK. We are examining the relation between breast feeding and the later development of asthma and atopy using objective measures of these phenotypes.