Validation of a Genomic Biomarker of Response to Environmental Tobacco Smoke

描述（由申请人提供）：二手烟草烟雾（SHS）对暴露个体的健康有深远的负面影响。在成年人中，SHS暴露的长期影响更为明显，SHS每年造成50，000人死亡。在儿童中，SHS的影响可能更为深远。暴露于SHS的儿童中位尼古丁代谢物水平是成人的两倍，SHS暴露是儿童发病的重要来源;导致下呼吸道疾病;咳嗽，痰，喘息和呼吸困难;中耳疾病;和肺功能水平较低。SHS的健康后果的研究领域的一个关键需求是开发有效的工具来评估早期的生物反应SHS。这些工具可以促进对SHS暴露反应差异的原因和后果的快速洞察;并且，与SHS暴露水平的直接测量不同，还可以用于评估干预措施的可能长期健康影响，以尽量减少儿童和成人的SHS暴露。 使用全基因组微阵列技术评估mRNA和miRNA表达，以及烟草烟雾产生气道上皮细胞损伤的概念，我们开发了创新的基因组生物标志物，通过分析可以使用微创程序从口腔或鼻腔收集的细胞来评估对SHS的生物反应。这些生物标志物将多个基因或miRNA的表达水平联合收割机组合成烟草烟雾暴露的复合量度，从而放大烟草烟雾信号，同时抑制个体基因的否则有噪声的表达水平。初步研究表明，在颊或鼻上皮细胞中测量的表达生物标志物将SHS暴露的年轻人与未暴露的个体区分开来。本文提出的研究将验证这些生物标志物，以评估参与CCCEH、DISCOVER和ASTHMA-DIET队列的80名SHS暴露儿童和80名未暴露儿童对SHS的生物学反应。来自鼻或颊上皮mRNA或miRNA表达的基于微阵列的测量的烟草烟雾暴露的生物标志物将与来自问卷、空气采样和可替宁的SHS暴露的测量进行比较。将通过6个月后对40名儿童重复采样来评估基因组生物标志物测量的重复性。 拟议的研究应用创新工具来测量对SHS暴露的生物学反应，这些生物学反应涉及多个已建立的队列，这些队列具有仔细表征的暴露，包括有SHS相关疾病风险的儿童。这些研究汇集了一个在肺部医学，流行病学，基因组学和生物统计学方面具有专业知识的团队，对了解烟草烟雾反应的长期兴趣，以及有效合作的既定记录，在建立将这些SHS暴露评估工具应用于大规模流行病学和基因环境研究的潜力和可行性方面迈出了关键的一步。通过测量对暴露的反应，而不是暴露本身，这些研究有可能广泛改变环境暴露影响研究的范式。

DESCRIPTION (provided by applicant): Second-hand tobacco-smoke (SHS) has a profoundly negative impact on the health of exposed individuals. In adults, where the long-term impacts of SHS exposure are more apparent, SHS is responsible for 50,000 deaths annually. In children, the effects of SHS are likely even more profound. Children exposed to SHS have median nicotine metabolite levels twice those of adults, and SHS exposure is a substantial source of childhood morbidity; resulting in lower respiratory illnesses; cough, phlegm, wheeze, and breathlessness; middle ear disease; and a lower level of lung function. A critical need in the area of research into the health consequences of SHS is the development of effective tools for assessing the early biological response to SHS. These tools could facilitate rapid insights into the causes and consequences of differences in the response to SHS exposure; and, unlike direct measures of SHS exposure levels, could also be used to assess the likely long-term health effects of interventions to minimize SHS exposure in both children and adults. Using genome-wide microarray technologies for assessing mRNA and miRNA expression together with the concept that tobacco smoke creates an airway-wide field of epithelial cell injury, we have developed innovative genomic biomarkers to assess the biologic response to SHS by profiling cells that can be collected from the mouth or nose using minimally invasive procedures. These biomarkers combine the expression levels of multiple genes or miRNAs into composite measures of tobacco-smoke exposure thereby amplifying the tobacco-smoke signal while dampening the otherwise noisy expression levels of individual genes. Preliminary studies show that expression biomarkers measured in buccal or nasal epithelium distinguish young adults with SHS exposure from unexposed individuals. The studies proposed here will validate these biomarkers for assessing the biological response to SHS in 80 SHS-exposed and 80 unexposed children participating in the CCCEH, DISCOVER and ASTHMA-DIET cohorts. Biomarkers of tobacco-smoke exposure derived from microarray-based measurements of nasal or buccal epithelial mRNA or miRNA expression will be compared to measures of SHS exposure derived from questionnaire, air sampling and cotinine. The repeatability of the genomic biomarker measurements will be assessed by repeat sampling of 40 children after 6 months. The proposed research applies innovative tools for measuring the biological response to SHS exposure to multiple established cohorts with carefully characterized exposures, including children at risk for SHS-related disease. The studies bring together a team with expertise in pulmonary medicine, epidemiology, genomics, and biostatistics, a long-term interest in understanding responses to tobacco smoke, and an established record of effective collaboration, to take a critical step in establishing the potential and feasibility of applying these SHS-exposure assessment tools to large-scale epidemiology and gene-environment studies. By measuring the response to exposure, rather than the exposure itself, these studies have the potential to broadly change the paradigm for research into the effects of environmental exposures.