Genetic And Environmental Factors In Childhood Respiratory Health

儿童呼吸系统健康的遗传和环境因素

• 批准号: 7734448
• 负责人: STEPHANIE JOAN LONDON
• 金额: $ 23.66万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7734448
• 关键词: Address; Age; Air Pollutants; Air Pollution; Allergens; Asthma; Bayesian Analysis; Birth; Blood specimen; Breast Feeding; Breathing; Burn injury; Candidate Disease Gene; Causations; Child; Childhood; Childhood Asthma; Cities; Collaborations; DNA; Data; Data Analyses; Data Collection; Data Set; Developed Countries; Developing Countries; Development; Environment; Environmental Risk Factor; Environmental Tobacco Smoke; Epidemiology; Epigenetic Process; Etiology; Exposure to; Extrinsic asthma; Family Study; Family history of; Feedback; Folate; Funding; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genotype; Goals; Haplotypes; Health; Heating; Human; Hypersensitivity; Inbred Strains Mice; Incidence; Infant; Intake; Journals; Life; Link; Literature; Mails; Manuscripts; Measures; Methods; Mexico; Mothers; Motivation; North America; Norway; Obesity; Omega-3 Fatty Acids; Online Systems; Outcome; Oxidants; Ozone; Paper; Parents; Patient Self-Report; Patient currently pregnant; Phenotype; Physicians; Physiological; Pilot Projects; Play; Population; Pregnancy; Pregnant Women; Public Health; Publication Bias; Publications; Published Comment; Publishing; Quality Control; Questionnaires; Rate; Registries; Reporting; Research; Research Personnel; Resources; Risk Factors; Role; Running; Sample Size; Sampling; Single Nucleotide Polymorphism; Stratification; Surveys; Testing; Triad Acrylic Resin; Wheezing; Wood material; Work; atopy; base; cohort; computing resources; cost; design; early childhood; experience; follow-up; gene environment interaction; gene interaction; genetic linkage; genome wide association study; novel; pollutant; positional cloning; prescription document; prescription procedure; prospective; protective effect; research clinical testing; respiratory; response; trafficking

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. In the past year our work in this study has focused on whole genome genotyping of these samples using the Illumina 550,000 single nucleotide polymorphism platform. We recently received the complete data set and have been doing the extensive data quality control needed before we can run analyses. Because no one at NIEHS has previously done similar analyses, we have had to develop expertise in new analytic methods and in developing computing resources to perform these analyses. We have also enlisted the assistance of various outside collaborators with experience in genome wide association studies. In addition, we are participating in a collaborative group recently established by NHLBI to combine genome wide association data already generated from all US studies to date. This will enable each study to overcome sample size limitations and also provide convenient replication of results across studies. It is important to evaluate candidate genes that have emerged from previous studies. Prior to beginning our whole genome genotype, we examined associations with an asthma gene that had been identified by positional cloning (GPRA). We found no clear association with this gene and in looking closely at the previous literature, it does not appear that this gene has replicated consistently in association studies. Although positive replication has been reported by several authors, the lack of association with the same SNPs and haplotypes across studies and the near certainty of positive publication bias do not give strong evidence for replication. This work was published in the past year (Wu et al., 2008). Increasing evidence suggest the importance of pregnancy and early life factors in the etiology of asthma and allergy in childhood. Various investigators in the Epidemiology Branch have established a collaboration with the Norwegian Mother and Child Cohort (called MoBa), a population based cohort of approximately 100,000 pregnant women in Norway who are being followed until their children reach adulthood. I have established a collaboration with the asthma group in Norway around gene-environment interaction and epigenetics. NIEHS/DIR partially supports the MoBa study with the goal of enabling such add-on studies. I have been working on analyses of early childhood outcomes with the MoBa investigators. In the current year we have had two of these publication accepted. In addition, I have been working closely with the Norwegian investigators to develop follow-up of the children at age seven. At this age, asthma can be reliably identified. We developed and pilot tested a follow-up questionnaire for mailing to parents of children who have turned seven. The first pilot study identified an acceptable response rate. We will revise the questionnaire based on subject and data manager feedback and will next test the feasibility of offering a web-based alternative to the paper questionnaire to decrease costs for follow-up of the entire cohort. We also plan to validate self-reports of asthma by linking to the new Norwegian prescription registry. To further validate these outcome and obtain later childhood asthma phenotypes we are planning clinical evaluation of subsets of the children based on their responses to the seven year mailed questionnaire. These follow-up activities will form the basis for high quality, well powered studies of interactions between genetics/epigenetics and the environment. In the past year we have identified a novel association between higher intake of folate in pregnancy and increased incidence of some early respiratory outcomes in the children (manuscript under review). This finding is an important motivation to follow the children to age seven to examine possible associations with asthma. In addition, this finding has motivated us to begin developing studies of epigenetic changes as a function of maternal levels of folate and other methyl donors during pregnancy. With my input, Dr. Siri Haberg has obtained Norwegian funding to come to NIEHS to work with me during a postdoctoral year to develop this project. While the MoBa study will yield important data on early life factors in asthma, as explained above, this is a long term project to be pursued as the children mature. To examine important questions regarding early life factors in asthma, I developed a collaboration with a birth cohort in the UK of approximately 14,000 children called ALSPAC. Although a substantial body of evidence supports a protective effect of breastfeeding on early childhood wheezing, some recent studies suggest that breastfeeding may be deleterious with respect to later childhood asthma and some early atopic phenotypes. However, these findings were sometimes seen in data subsets in studies underpowered for such analyses. Because of the public concern about whether breastfeeding might increase asthma incidence, we examined the relation between breastfeeding and several objective measures of atopy and asthma in later childhood in the ALSPAC study. This is the largest study to date with prospective data on breastfeeding and objective measures of atopy and bronchial hyperresponsiveness. We found no evidence that breastfeeding has deleterious effects on any outcome. A major benefit of this study is the large sample size which give substantial power, even upon stratification by other factors such as maternal atopy. Furthermore, the prospective data collection enabled us to address potential reverse causation, whereby early manifestations of asthma phenotypes might influence the duration of breastfeeding. This possible bias has been only rarely examined. Although we did find evidence that mothers of infants with wheezing in the first few months of life breast fed these children longer, using a Bayesian analysis we did not find evidence for bias in the association between breastfeeding and asthma phenotypes. We believe that these findings are strong evidence that breastfeeding is not a risk factor for childhood asthma and should reassure pregnant mothers and their physicians regarding this practice. The work has been published in the past year and featured with a commentary by the journal because of the public health importance of the findings (Elliot et al., 2008). I have also been working with Dr. Darryl Zeldin and others on analyses of data collected with NIEHS intramural funding within the National Health Examination Survey (NHANES) 2005-2006. I am collaborating on analyses of obesity as a risk factor for asthma and allergy and plan to pursue analyses of air pollution and allergen levels as these data become available.

主要项目是对墨西哥城市高度暴露的人口中对哮喘的遗传敏感性的家庭研究。这项研究使用了案例三合会设计。在过去的一年中，我们在这项研究中的工作集中在使用Illumina 550,000单核苷酸多态性平台的这些样品的整个基因组基因分型上。我们最近收到了完整的数据集，并在进行分析之前一直在进行所需的广泛数据质量控制。由于NIEHS以前没有人进行过类似的分析，因此我们必须在新的分析方法和开发计算资源以执行这些分析方面发展专业知识。我们还为各种外部合作者提供了基因组广泛协会研究经验的协助。此外，我们还参加了NHLBI最近成立的一个合作小组，以结合迄今为止所有美国研究已经产生的基因组广泛的关联数据。这将使每项研究能够克服样本量的限制，并在整个研究中提供方便的结果复制。评估先前研究中出现的候选基因很重要。在开始我们的整个基因组基因型之前，我们检查了与位置克隆（GPRA）鉴定的哮喘基因的关联。我们发现与该基因没有明确的关联，并且在仔细研究以前的文献时，似乎并未在关联研究中始终如一地复制。尽管几位作者已经报道了积极的复制，但在研究中与相同的SNP和单倍型缺乏关联，并且近乎阳性偏见的近乎确定性并不能提供强有力的复制证据。这项工作在过去的一年中发表（Wu等，2008）。 越来越多的证据表明，怀孕和早期生命因素在童年时期的哮喘和过敏病因中的重要性。流行病学分支机构的各种研究人员与挪威的母亲和儿童队列（称为MOBA）建立了合作，这是一个基于人口的同类，在挪威约有100,000名孕妇，他们一直受到关注，直到他们的孩子成年。我已经与挪威的哮喘小组建立了一个围绕基因环境互动和表观遗传学的合作。 NIEHS/DIR部分支持MOBA研究，目的是实现此类附加研究。我一直在与MOBA调查人员进行幼儿结局的分析。在当年，我们接受了其中两个出版物。此外，我一直与挪威调查人员紧密合作，以对七岁的儿童进行后续行动。在这个年龄，可以可靠地识别哮喘。我们开发并试点测试了一份后续调查表，以邮寄给已经七岁的孩子的父母。第一个试点研究确定了可接受的响应率。我们将根据主题和数据经理的反馈来修改问卷，然后测试提供基于Web的纸质替代纸质问卷的可行性，以降低整个队列的随访成本。我们还计划通过链接到新的挪威处方注册表来验证哮喘的自我报告。为了进一步验证这些结果并获得后期的童年哮喘表型，我们正在根据孩子对七年邮寄问卷的回答计划对儿童的子集进行临床评估。这些后续活动将构成对遗传学/表观遗传学与环境之间相互作用的高质量，有力研究的基础。 在过去的一年中，我们已经确定了叶酸在妊娠中的较高摄入量与儿童早期呼吸系统结局的发病率增加（手稿）。这一发现是跟随儿童到7岁以检查可能与哮喘的关联的重要动机。此外，这一发现激发了我们开始对怀孕期间叶酸和其他甲基供体水平的表观遗传变化的研究。有了我的意见，Siri Haberg博士获得了挪威的资金，在博士后年，来到Niehs与我合作，以开发该项目。 如上所述，虽然MOBA研究将产生有关哮喘早期生命因素的重要数据，但这是一个长期的项目，可以作为孩子成熟。为了研究有关哮喘早期生命因素的重要问题，我与英国的一个出生队列进行了合作，约有14,000名名为ALSPAC的儿童。尽管大量证据支持母乳喂养对幼儿喘息的保护作用，但最近的一些研究表明，母乳喂养在幼儿哮喘和一些早期特应性表型方面可能是有害的。但是，这些发现有时在数据子集中看到的研究不足以进行此类分析。由于公众对母乳喂养是否可能增加哮喘发病率的关注，因此我们在ALSPAC研究中研究了母乳喂养与童年后期的几种客观的特应性和哮喘的关系。这是迄今为止最大的研究，其中有关于母乳喂养以及应对特应性和支气管高反应性的客观度量的前瞻性数据。我们没有发现母乳喂养对任何结果都有有害影响。这项研究的一个主要好处是，即使在其他因素（例如母体特温）分层的情况下，较大的样本量也具有很大的能力。此外，前瞻性数据收集使我们能够解决潜在的逆向因果关系，从而提前表现出哮喘表型的早期表现可能会影响母乳喂养的持续时间。这种可能的偏见很少受到检查。尽管我们确实发现了证据表明，在生命的头几个月，母乳喂养这些儿童的母亲的母亲使用贝叶斯分析，但我们没有发现母乳喂养和哮喘表型之间关联的偏见证据。我们认为，这些发现是有力的证据表明，母乳喂养不是儿童哮喘的危险因素，因此应该向怀孕的母亲及其医生对这种做法保证。这项工作已于过去一年发表，并在《杂志》中发表了评论，因为这些发现的公共健康重要性（Elliot等，2008）。 我还一直与Darryl Zeldin博士和其他人合作，分析了2005- 2006年国家健康检查调查（NHANES）中使用NIEHS内部资金收集的数据。我正在合作将肥胖症分析作为哮喘和过敏的危险因素，并计划在这些数据可用时进行空气污染和过敏原水平的分析。

项目成果

Parental smoking modifies the relation between genetic variation in tumor necrosis factor-alpha (TNF) and childhood asthma.

• DOI: 10.1289/ehp.9740
• 发表时间: 2007-04
• 期刊: Environmental health perspectives
• 影响因子: 10.4
• 作者: Wu H;Romieu I;Sienra-Monge JJ;del Rio-Navarro BE;Anderson DM;Dunn EW;Steiner LL;Lara-Sanchez Idel C;London SJ
• 通讯作者: London SJ

Ozone exposure, vitamin C intake, and genetic susceptibility of asthmatic children in Mexico City: a cohort study.

• DOI: 10.1186/1465-9921-14-14
• 发表时间: 2013-02-04
• 期刊: Respiratory research
• 影响因子: 5.8
• 作者: Moreno-Macías H;Dockery DW;Schwartz J;Gold DR;Laird NM;Sienra-Monge JJ;Del Río-Navarro BE;Ramírez-Aguilar M;Barraza-Villarreal A;Li H;London SJ;Romieu I
• 通讯作者: Romieu I

Breastfeeding and asthma in adolescents.

青少年的母乳喂养和哮喘。

• DOI: 10.2105/ajph.94.11.1843
• 发表时间: 2004
• 期刊: American journal of public health
• 影响因子: 12.7
• 作者: London,StephanieJ;Promislow,JoanneHE
• 通讯作者: Promislow,JoanneHE

Gene-air pollution interactions in asthma.

• DOI: 10.1513/pats.200701-031aw
• 发表时间: 2007-07-01
• 期刊: Proceedings of the American Thoracic Society
• 作者: London, Stephanie J

Genetic polymorphism of GSTM1 and antioxidant supplementation influence lung function in relation to ozone exposure in asthmatic children in Mexico City.

• 发表时间: 2004
• 期刊: Thorax
• 影响因子: 10
• 作者: I. Romieu;S. Jj;Matiana Ramírez-Aguilar;H. Moreno-Macías;N. I. Reyes-Ruiz;B. D. Río-Navarro;M. Hernández-Ávila;S. London