Validation of a Genomic Biomarker of Response to Environmental Tobacco Smoke

描述(由申请人提供)：二手烟烟雾(SHS)对接触二手烟的人的健康有深远的负面影响。在成年人中，SHS暴露的长期影响更明显，SHS每年造成50,000人死亡。在儿童中，SHS的影响可能更深远。暴露于SHS的儿童尼古丁代谢物的中位数是成人的两倍，SHS暴露是儿童发病率的重要来源；导致下呼吸道疾病；咳嗽、咳痰、喘息和呼吸困难；中耳疾病；以及肺功能低下。在研究SHS对健康的影响方面，迫切需要开发有效的工具来评估SHS的早期生物学反应。这些工具有助于快速了解对SHS暴露的反应差异的原因和后果；而且，与SHS暴露水平的直接测量不同，这些工具还可以用来评估干预措施可能产生的长期健康影响，以最大限度地减少儿童和成人的SHS暴露。使用全基因组微阵列技术来评估mRNA和miRNA的表达，以及烟草烟雾造成呼吸道广泛的上皮细胞损伤的概念，我们开发了创新的基因组生物标记物，通过分析可以使用微创程序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miRNAs的表达水平组合成烟草烟雾暴露的综合衡量标准，从而放大烟草烟雾信号，同时抑制个别基因的噪声表达水平。初步研究表明，在口腔或鼻上皮中测量的表达生物标记物将暴露于SHS的年轻人与未暴露的人区分开来。这里提出的研究将验证这些生物标记物，用于评估参与CCCEH、DISCOVER和哮喘饮食队列的80名SHS暴露儿童和80名非暴露儿童对SHS的生物反应。从基于微阵列的鼻腔或颊上皮细胞mRNA或miRNA表达的测量中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。基因组生物标记物测量的重复性将在6个月后通过对40名儿童的重复抽样进行评估。拟议的研究应用了创新的工具来衡量SHS暴露在多个已建立的队列中的生物学反应，这些队列具有仔细描述的暴露特征，包括有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、对了解烟草烟雾的反应具有长期兴趣并已有有效合作记录的团队，以确定将这些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。通过衡量对暴露的反应，而不是暴露本身，这些研究有可能广泛改变环境暴露影响的研究范式。

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.