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。在接触二手烟的长期影响更为明显的成年人中，二手烟每年造成5万人死亡。在儿童中，SHS的影响可能更为深远。暴露于二手烟的儿童尼古丁代谢物的中位数水平是成人的两倍，二手烟暴露是儿童发病的一个重要来源；导致下呼吸道疾病；咳嗽、痰多、喘息、呼吸困难；中耳疾病；肺功能也较低。在研究二手烟对健康的影响方面，迫切需要开发有效的工具来评估对二手烟的早期生物反应。这些工具可促进迅速了解对接触有毒物质的不同反应的原因和后果；而且，与直接测量SHS暴露水平不同，还可用于评估为尽量减少儿童和成人的SHS暴露而采取的干预措施可能对健康产生的长期影响。利用全基因组微阵列技术评估mRNA和miRNA的表达，结合烟草烟雾会造成全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，通过分析可使用微创手术从口腔或鼻子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的表达水平结合到烟草烟雾暴露的复合测量中，从而放大烟草烟雾信号，同时抑制个别基因的其他嘈杂表达水平。初步研究表明，口腔或鼻上皮中表达的生物标志物可以区分暴露于SHS的年轻人和未暴露的个体。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暴露和80名未暴露儿童对SHS的生物学反应。通过基于微阵列的鼻或颊上皮mRNA或miRNA表达测量得出的烟草烟雾暴露的生物标志物将与通过问卷调查、空气采样和可替宁得出的SHS暴露的测量结果进行比较。基因组生物标志物测量的可重复性将通过在6个月后对40名儿童进行重复采样来评估。拟议的研究应用创新工具来测量多个已建立的具有仔细特征暴露的队列对SHS暴露的生物学反应，包括具有SHS相关疾病风险的儿童。这些研究汇集了一支在肺部医学、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，他们对了解对烟草烟雾的反应有长期兴趣，并建立了有效合作的记录，从而在确定将这些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地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.