Genetic And Environmental Factors In Childhood Respirato

长期以来，哮喘一直被认为是家族性的。最近，进行了连锁研究，以确定涉及的特定基因。然而，随着多个联系区域的确定，这项工作进展缓慢。很明显，基因-环境的相互作用在决定谁会患哮喘方面很重要。到目前为止，进行的联系研究还没有被设计成适当地探索相互作用。鉴于哮喘的复杂性质，显然有必要进行候选基因关联研究，以确定疾病基因及其与环境因素的相互作用。 长期以来，空气污染在哮喘恶化中的作用一直受到重视。臭氧是一种氧化性空气污染物，是会加重现有哮喘的因素之一。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。最近在动物身上进行的关联研究开始确定与臭氧和其他吸入污染物的特定生理反应有关的基因。 该项目包括几项研究，包括遗传多态、环境因素及其相互作用在儿童呼吸系统疾病病因学中的作用。主要项目是对墨西哥城臭氧暴露程度较高的人群进行哮喘遗传易感性的家庭研究。本研究采用个案-父母三合会设计。我们正在积极地对这些样本进行遗传分析。 我已经与两个出生队列建立了合作关系，研究哮喘病因中的早期生活因素。在ALSPAC的研究出生队列中，我们正在研究母乳喂养与特应性和哮喘的客观指标之间的关系。我还在与挪威和其他欧洲的哮喘研究人员合作，在挪威母婴队列(简称MOBA)内建立一个哮喘研究项目。MOBA是一个以人口为基础的队列，由挪威的10万名孕妇组成，她们一直被跟踪，直到她们的孩子成年。哮喘项目将围绕基因与环境的相互作用展开。NIEHS/DIR部分支持MOBA研究，目的是使这种附加研究成为可能。作为开发这一项目的背景，我正在分析队列中的数据，以跟进文献中公认的发现，即出生顺序较晚的孩子患哮喘的风险降低。这被归因于在所谓的“卫生假说”下，较晚出生的儿童有更大的儿童期感染。然而，较晚出生的孩子的宫内环境也可能与他们的大兄弟姐妹不同。因为MOBA是为数不多的几项研究之一，其中包括登记了不止一次怀孕的女性，所以我正在研究与子女哮喘风险相关的暴露是否在一次怀孕到下一次怀孕之间发生变化，以及母亲的特应性状态是否在怀孕期间发生变化。与我建立合作关系的另一个群体是ALSPAC，这是英国雅芳的一个出生群体，由1.2万名女性组成。我们正在使用这些表型的客观测量方法来研究母乳喂养与哮喘和特应性疾病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.