Genetic variation and biomarkers in children with acute lung injury

描述(由申请人提供)： 确定哪些儿童患急性肺损伤(ALI)和急性呼吸窘迫综合征(ARDS)的风险最大，对于开始早期治疗和限制与这些疾病相关的急性和长期发病率以及高死亡率(估计为20%-50%)至关重要。ALI/ARDS发生在具有特定临床条件的儿童身上，包括肺炎、吸入或败血症。不幸的是，在这一高危人群中确定最有可能发生ALI/ARDS的儿童是困难的。目前还没有大型的、强有力的研究来检验肺损伤儿童的特定遗传变异或血浆生物标记物是否与进展为ALI/ARDS的可能性增加有关。这项建议是一项大型、多机构临床试验的辅助研究，该试验招募了大约2800名患有实质性肺部疾病的插管儿童。这项建议中描述的研究将在父母研究的队列中比较患有ALI/ARDS的儿童和那些没有发展为ALI/ARDS的儿童特定候选基因和血浆生物标记物的遗传变异。这群高危儿童比迄今为止研究过的任何儿童都多得多。我们的假设是，与那些没有发生ALI/ARDS的插管儿童相比，发生ALI/ARDS的插管儿童在候选基因中具有不同频率的特定基因变异，并改变与这些基因相对应的血浆生物标志物的水平。在这个庞大的插管儿童队列中，这些独特的比较将包括以下分析：1)涉及炎症、凝血和表面活性物质合成的选定候选基因的遗传变异，以及2)选定的炎症、凝血和表面活性物质的血浆生物标记物。这一辅助方案的主要结果衡量标准是ALI/ARDS的进展情况。这项建议的另一个独特之处是，该队列将被分成高加索人和非裔美国人两个亚组进行分析。如果利用这项研究的结果可以确定ALI/ARDS风险更高的儿童，未来的研究将被设计来确定这些信息是否可以用于早期识别患有ALI/ARDS高危儿童患者，从而允许更早地启动特定的肺保护策略，从而降低死亡率、更少的机械通气天数、更短的重症监护和住院时间以及更低的医院成本。此外，这项建议的结果将进一步深入了解儿童ALI/ARDS的病理生理学。公共卫生相关性：确定哪些儿童患急性肺损伤(ALI)和急性呼吸窘迫综合征(ARDS)的风险最大，对于开始早期治疗和限制与这些疾病相关的急性和长期发病率以及高死亡率至关重要。ALI/ARDS发生在具有特定临床条件的儿童身上，包括肺炎、吸入或败血症。然而，对这些临床情况的反应在不同的人之间是不同的，一些儿童恢复时没有并发症，而另一些儿童则继续发展为ALI/ARDS。不幸的是，在这一高危人群中确定最有可能发生ALI/ARDS的儿童是困难的。该提案将研究个体的基因构成是否可能影响儿童ALI/ARDS的发展，以及/或者特定的血浆生物标记物是否有助于识别将进展为严重肺损伤的儿童。识别影响肺损伤严重程度或预测哪些儿童将进展为更严重的肺损伤的遗传变异和生物标志物可能有助于更好地了解ALI/ARDS的病理生理学，有助于识别哪些儿童可能处于更高的ALI/ARDS发展风险，并可能确定新的治疗靶点。(摘要结束)

DESCRIPTION (provided by applicant): Identifying children who have the greatest risk for the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is crucial to beginning early therapies and limiting acute and long- term morbidity and the high mortality (estimated at 20-50%) associated with these conditions. ALI/ARDS develops in children with specific clinical conditions, including pneumonia, aspiration, or sepsis. Unfortunately, identifying children with the greatest likelihood of developing ALI/ARDS within this high risk population is difficult. There have been no large, well-powered studies examining whether specific genetic variants or plasma biomarkers in children with lung injury are associated with the increased likelihood of progressing to ALI/ARDS. This proposal is an ancillary study to a large, multi-institutional clinical trial enrolling approximately 2800 intubated children with parenchymal lung disease. The study described in this proposal will compare genetic variations in specific candidate genes and plasma biomarkers in those children who develop ALI/ARDS with those who do not develop ALI/ARDS within the cohort of the parent study. This cohort of at risk children is much larger than any that has been studied to date. Our hypothesis is that intubated children with parenchymal lung disease who develop ALI/ARDS will have different frequencies of specific genetic variants in candidate genes and altered levels of plasma biomarkers corresponding to these genes compared with those intubated children who do not develop ALI/ARDS. These unique comparisons in this large cohort of intubated children will include an analysis of: 1) genetic variations in selected candidate genes involved in inflammation, coagulation and surfactant synthesis and 2) selected plasma biomarkers of inflammation, coagulation and surfactant. The primary outcome measure for this ancillary proposal is the development of ALI/ARDS. Another unique aspect of this proposal is that the cohort will be stratified into Caucasian and African American subgroups for analyses. If children at greater risk for ALI/ARDS can be identified using the findings from this study, future studies would be designed to determine whether the information could be used for early identification of pediatric patients at high risk for development of ALI/ARDS thereby allowing earlier initiation of specific lung protective strategies leading to lower mortality, fewer days of mechanical ventilation, shorter intensive care and hospital length of stay, and lower hospital costs. In addition, results from this proposal will provide further insight into the pathophysiology of ALI/ARDS in children. PUBLIC HEALTH RELEVANCE: Identifying children who have the greatest risk for the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is crucial to beginning early therapies and limiting acute and long-term morbidity and the high mortality associated with these conditions. ALI/ARDS develops in children with specific clinical conditions, including pneumonia, aspiration, or sepsis. However, the response to these clinical conditions is variable between different individuals with some children recovering without complications while others go on to develop ALI/ARDS. Unfortunately, identifying children with the greatest likelihood of developing ALI/ARDS within this high risk population is difficult. This proposal will examine whether an individual's genetic make-up might influence the development of ALI/ARDS in children and/or whether specific plasma biomarkers may help identify those children who will progress to develop severe lung injury. Identifying genetic variants and biomarkers that influence the severity of lung injury or predict which children will progress to more severe lung injury may help better understand the pathophysiology of ALI/ARDS, help identify children who may be at greater risk for the development of ALI/ARDS, and perhaps identify novel therapeutic targets. (End of Abstract)