University of Washington
Grant: $3,103,446 - National Institutes of Health - Sep. 24, 2009
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Award Description: Specific Aims: Acute Lung Injury (ALI) is a common complication of sepsis and trauma and is associated with mortality of over 20%. Candidate gene studies suggest a role for common genetic variation in determining host susceptibility to ALI in critically ill patients. However, variants studied to date account for only a small proportion of the variability in risk of an individual to develop ALI after exposure to apparently similar risk factors such as sepsis or traumatic injury. We hypothesize that additional common genetic variants associated with increased risk for ALI can be discovered in a large group of patients at-risk for ALI using a genome-wide association study (GWAS). We propose to capitalize on existing genomic DNA samples and associated rich phenotypic data collected as part of the ARDSnet consortium clinical trials in this genome-wide search for ALI risk alleles. We will leverage well-phenotyped samples collected as part of studies performed by members of the iSPAAR (identification of SNPs Predisposing to Altered ALI Risk) consortium to provide an unprecedented sample size for a genetic study in the critically ill. Through the following specific aims we will provide new insight on ALI pathogenesis and identify novel markers of risk for ALI that can be tested in future studies for utility in risk stratification and identification of subjects at high-risk for poor outcomes that might benefit most from new therapeutic interventions. Aim 1: In a discovery phase, identify common genetic markers of risk for ALI and ALI-related outcomes using genome-wide genotyping in ALI cases from ARDSnet and matched at-risk controls from the iSPAAR consortium. Hypothesis 1a) Comparison of genotype frequencies between cases of ALI from ARDSnet studies and at-risk controls from the iSPAAR consortium population matched for race, ALI risk, non-ALI inclusions, and absence of major exclusions will identify novel potential genetic markers of risk for ALI. Hypothesis 1b) Comparison of genotype frequencies between survivors and non-survivors at 28 days in cases of ALI from ARDSnet will identify novel potential genetic markers of risk for ALI-related death. Hypothesis 1c) Common genetic variants will be associated with more severe disease in cases of ALI from ARDSnet as measured by ventilator-free days, ICU-free days, and acute kidney injury (AKI) stage. Aim 2: In a validation phase, we will test whether the ~5,000 markers showing the strongest associations with ALI susceptibility and outcomes in the discovery phase can be validated in either sepsis-associated ALI or trauma-associated ALI and at-risk controls from the iSPAAR consortium using a nested case/control design. Hypothesis 2a) A subset of the genetic markers identified in Aim 1 (Hypotheses 1a)-c)) as associated with susceptibility to ALI and related outcomes will be validated in subjects from the iSPAAR consortium with sepsis who do (cases) or do not (controls) develop ALI. Hypothesis 2b) A subset of the genetic markers identified in Aim 1 (Hypotheses 1a)-c)) as associated with susceptibility to ALI and related outcomes will be validated in subjects from the iSPAAR consortium admitted with trauma who do (cases) or do not (controls) develop ALI. Hypothesis 2c) A subset of the genetic markers will be identified that validate in both Hypothesis 2a) and 2b) and will be associated with ALI and ALI-related outcomes regardless of underlying risk factor. Aim 3: In a functional evaluation phase, we will test whether the genetic markers validated in Aim 2 are associated with circulating biomarkers in ARDSnet and iSPAAR subjects or are associated with gene or protein expression in two in vitro systems. Hypothesis 3a) Genetic markers validated in Aim 2 will be associated with levels of circulating biomarkers relevant to ALI pathogenesis measured in the serum of subjects from ARDSnet and iSPAAR. Hypothesis 3b) Genetic markers validated in Aim 2 will be associated with the lev
Project Description: Project recently awarded; no activity to date.
Jobs Summary: Not Applicable this Quarter (Total jobs reported: 0)
Project Status: Not Started
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