Genetic Influence on Incidence of Acute Lung Injury

该项目的目标是确定特定抗氧化剂基因中的功能基因多态和/或单倍型，这些基因与严重创伤患者中急性肺损伤(ALL)及其更严重的形式-急性呼吸窘迫综合征(ARDS)的风险增加相关。我们假设，改变调节氧化剂产生和解毒作用的酶的功能的基因变异将增加经历过重大创伤的危重患者发生ALI/ARDS的风险。目前的建议建立在我们已建立的队列研究基础设施的基础上，该基础设施是由我们的团队开发和完善的，作为ALI/ARDS先前NHLBI SCOR的一部分。两个关键的抗氧化剂基因(过氧化氢酶和GSTpi)将根据实验数据进行检查，这些数据表明它们在肺部疾病中发挥重要作用，初步分析表明单核苷酸多态(SNPs)与ALI/ARDS风险增加有关。由于越来越多的证据表明1-半胱氨酸过氧化还蛋白(PRDX6)在保护氧化损伤中的重要性以及该酶在PO1提案中的中心位置，因此将对该酶进行研究。在目标1中，将对90名健康志愿者进行过氧化氢酶、GSTpi和PRDX6基因的基因和单倍型结构测定。单倍型 生成的结构将被用来在AIM 2中测试与ALI/ARDS风险的相关性，并指导AIM 3的功能分析。在AIM 2中，将使用我们的主要创伤队列研究中估计的635名受试者(273名已经登记，362名待登记)来确定过氧化氢酶、GSTpi和PRDX6候选SNP与ALI/ARDS风险的相关性。将研究单个SNP、单倍型和基因交互作用之间的关联。在目标3中，将使用基于细胞和动物的模型来确定候选基因中观察到的SNPs的功能意义。这一建议将增加对ALI/ARDS发病机制的遗传学基础的理解，并增加这些基因如何与其他相关临床风险因素相互作用的知识。这项研究的结果可能被用来建议旨在预防高危人群ALI/ARDS的基因筛查策略。最后，这项队列研究将在未来的研究中作为一个有价值的资源来测试氧化应激调节因子与ALI/ARDS中其他病理生理通路的相互作用。

The goal of this project is to identify functional gene polymorphisms and/or haplotypes in specific antioxidant genes that are associated with an increased risk of Acute Lung Injury (ALl) and its more severe form, the Acute Respiratory Distress Syndrome (ARDS), among patients with major trauma. We hypothesize that genetic variations that alter the function of enzymes that regulate oxidant production and detoxification will increase the risk of ALI/ARDS in critically ill patients who have experienced major trauma. The current proposal builds on our established cohort study infrastructure that was developed and refined by our group as part of a previous NHLBI SCOR in ALI/ARDS. Two key anti-oxidant genes (catalase and GSTpi) will be examined based on experimental data suggesting they play an important role in lung disease and preliminary analyses suggesting an association of single nucleotide polymorphisms (SNPs) with increased ALI/ARDS risk. 1-cys peroxiredoxin (PRDX6) will be studied because of the mounting evidence suggesting the importance of this enzyme in protecting against oxidative damage and the central position of this enzyme in this PO1 proposal. In Aim 1, the gene and haplotype structure of the catalase, GSTpi, and PRDX6 genes will be determined in 90 healthy volunteers. Haplotype structures generated will be used to test associations with ALI/ARDS risk in Aim 2 and guide the functional analyses of Aim 3. In Aim 2, the association of candidate SNPs in catalase, GSTpi, and PRDX6 with risk of ALI/ARDS will be determined in patients who have experienced major trauma using an estimated 635 subjects in our major trauma cohort study (273 already enrolled and 362 to be enrolled). Association of single SNP's, haplotypes and genotype interactions will be examined. In Aim 3, the functional significance of observed SNPs in the candidate genes will be determined using cell and animal-based models. This proposal will add to the understanding of the genetic basis of ALI/ARDS pathogenesis and increase knowledge about how these genes interact with other relevant clinical risk factors. The findings of this study could potentially be used to suggest genetic screening strategies aimed at preventing ALI/ARDS in at-risk populations. Finally, this cohort study will serve as a valuable resource to test the interaction of regulators of oxidant stress with other pathophysiological pathways in ALI/ARDS in future studies.