Genetic And Environmental Factors In Childhood Respirato

目的：本项目的目的是检查影响儿童呼吸道疾病风险的遗传和环境因素，并评估基因与环境的相互作用。为此，我们汇集了一套三项针对学龄儿童的国际研究，这些儿童来自三个不同哮喘流行人群-武汉中国(低)、墨西哥城(中等)和美国南加州(高)。这三个地点提供了一系列可能与遗传易感性相互作用的环境因素的暴露。其中包括臭氧、内毒素和环境烟草烟雾。武汉市中国人群显著暴露于室内燃煤、环境烟草烟雾高流行和环境空气污染。墨西哥城的工厂以北美臭氧水平最高而闻名，内毒素水平也很高。南加州的这项研究提供了一系列具有良好特征的暴露于空气污染的环境。程序和技术：本项目中的三项研究是在设计略有不同的学龄儿童中进行的。武汉的这项研究是一项以学校为基础的研究，对象是1999年入学的22所学校的5051名七年级学生。我们收集了环境暴露和呼吸结果数据、肺功能和口腔细胞DNA。我们目前正在跟踪学生第三年的情况。墨西哥城的研究使用了案例-父母三合会的设计。我们在市中心的一家医院登记了7-17岁的哮喘儿童和他们的父母作为对照组。病例-父母三合一设计使得能够检查由于种族分层而产生的偏见的候选基因关联，这是墨西哥城两个人口组合中的一个潜在问题。病例-父母三合一设计还允许识别胎儿和母亲的遗传效应。墨西哥城的人口经历了北美最高的臭氧水平。周围环境的内毒素也升高了。我们正在基于人类和动物的证据，研究与臭氧呼吸反应有关的候选基因。南加州的研究是一项以学校为基础的空气污染队列研究，是我在来NIEHS之前帮助建立的。从1998年春天开始，我开始收集队列中的遗传物质，以检查哮喘和肺功能发育受损的候选基因。这一收藏非常成功，它被纳入了NIEHS/EPA儿童中心的赠款，现在得到了外部资金的资助。然而，我仍然作为合作者参与其中。我还在分析我为这项研究设计的问卷数据。成就：在武汉的研究中，我们正在完成对第一年的横断面数据的分析。我们发现，环境烟草烟雾与咳嗽的相关性最强，室内燃煤与喘鸣的相关性最强。这两种关系都表现出剂量效应。我们正在准备这份手稿以供提交。根据问卷数据，我们选择了病例和对照组进行遗传学研究，并开始对一组常见的候选基因进行基因分型，就像墨西哥城的研究一样。在墨西哥城的研究中，我们已经提取了200多个三联体的DNA，并正在完成对几个基因的多态性的基因分型，这些基因似乎与小鼠模型对臭氧的肺部反应有关。我们会继续招收三合会会员，直至达到五百名三合会会员的目标。在南加州的研究中，基因样本仍在收集中。然而，我们已经证明了基于哮喘和过敏家族史的基因-环境交互作用。在家族史阳性的受试者中，母亲孕期吸烟与早发性持续性哮喘的相关性最强。这一结果表明，早期生活环境暴露对遗传易感性儿童的危害可能更大。

Aims: The aim of this project is to examine genetic and environmental factors that influence the risk of childhood respiratory illnesses and to evaluate gene-environment interactions. To this end, we have assembled a set of three international studies of school aged children from populations with three different asthma prevalences - Wuhan China (low), Mexico City (intermediate) and Southern California, US (high). The three sites provide a range of exposures to environmental factors that are likely to interact with genetic susceptibility. These include ozone, endotoxin and environmental tobacco smoke. Notable exposures in the Wuhan China population are indoor coal burning, high prevalence of environmental tobacco smoke, and ambient air pollution. The Mexico City site is notable for the highest levels of ozone in North America and endotoxin levels are also high. The Southern California study offers a range of well characterized exposures to air pollution. Procedures and techniques: The three studies in this project are conducted among school aged children with slightly different designs. The Wuhan study is a school-based study of 5,051 seventh graders at 22 schools enrolled in 1999. We collected environmental exposure and respiratory outcome data, pulmonary function and DNA from buccal cells. We are currently following the students for the third year. The Mexico City study uses the case-parent triad design. We are enrolling asthmatic children aged 7-17 at an inner city hospital along with their parents as controls. The case-parent triad design enables the examination of candidate gene associations from bias due to ethnic stratification, a potential problem in the two population mix of Mexico City. The case-parent triad design also allows the discernment of fetal versus maternal genetic effects. This Mexico City population experiences the highest ozone levels in North America. Ambient endotoxin is also elevated. We are examining candidate genes involved in respiratory responses to ozone, based on human and animal evidence. The Southern California study is a school-based air pollution cohort study that I helped establish before coming to NIEHS. Beginning in the spring of 1998, I initiated a collection of genetic material on the cohort to examine candidate genes for asthma and impaired growth of pulmonary function. This collection was so successful that it was incorporated into an NIEHS/EPA Children's Center grant and is now extramurally funded. However, I remain involved as a collaborator. I am also analyzing data from questionnaires that I designed for this study. Accomplishments: In the Wuhan study, we are completing an analysis of cross-sectional data from the first year. We have found that environmental tobacco smoke is most strongly related to cough and indoor coal burning is most strongly related to wheeze. Both of these relationships show a dose-response. We are preparing this manuscript for submission. Based on the questionnaire data, we have selected cases and a comparison group for genetic studies and have begun genotyping for a common set of candidate genes as in the Mexico City study. In the Mexico City study, we have extracted DNA on over 200 triads and are completing genotyping for polymorphisms in several genes that appear to be involved in pulmonary response to ozone in mouse models. We will continue enrollment until a goal of 500 triads is reached. In the Southern California study, the genetic samples are still being collected. However, we have demonstrated a gene-environment interaction based on family history of asthma and allergy. Maternal smoking in pregnancy was most strongly related to early onset persistent asthma among family history positive subjects. This result suggests that early life environmental exposures may be more detrimental in genetically predisposed children.