Genetic Influence on Incidence of Acute Lung Injury

该项目的目标是确定与重大创伤患者急性肺损伤（ALl）及其更严重形式急性呼吸窘迫综合征（ARDS）风险增加相关的特定抗氧化基因的功能基因多态性和/或单倍型。我们假设，基因变异改变了调节氧化剂产生和解毒的酶的功能，将增加经历过重大创伤的重症患者发生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上，该基础设施是由我们的团队开发和完善的，是ALI/ARDS先前NHLBI SCOR的一部分。两个关键的抗氧化基因（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起重要作用，初步分析表明单核苷酸多态性（snp）与ALI/ARDS风险增加有关。由于越来越多的证据表明该酶在防止氧化损伤方面的重要性以及该酶在PO1提案中的中心地位，因此将对1-cys过氧化物还蛋白（PRDX6）进行研究。在Aim 1中，将测定90名健康志愿者过氧化氢酶、GSTpi和PRDX6基因的基因和单倍型结构。单体型

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.