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.
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