Genetic risks for ALI in ARDSnet and the iSPAAR Consortium

描述（由申请人提供）： 急性肺损伤（ALI）是脓毒症和创伤的常见并发症，死亡率超过20%。候选基因研究表明，常见的遗传变异在决定危重患者对ALI的易感性中起作用。然而，迄今为止研究的变异仅占个体在暴露于明显相似的风险因素（例如败血症或创伤性损伤）后发生ALI风险变异的一小部分。我们假设，使用全基因组关联研究（GWAS），可以在一大群有ALI风险的患者中发现与ALI风险增加相关的其他常见遗传变异。我们建议利用现有的基因组DNA样本和相关的丰富的表型数据收集的ARDSnet联盟临床试验的一部分，在这个全基因组搜索ALI风险等位基因。我们将利用作为iSPAAR（识别易感性改变ALI风险的SNP）联盟成员进行的研究的一部分收集的良好表型样本，为危重患者的遗传研究提供前所未有的样本量。通过以下具体目标，我们将提供有关ALI发病机制的新见解，并确定新的ALI风险标志物，这些标志物可以在未来的研究中进行测试，用于风险分层和识别可能从新的治疗干预措施中获益最多的不良结局高风险受试者。我们还将为研究ALI的遗传学潜在风险提供宝贵的新资源，这将促进许多未来的研究，这些研究以前由于缺乏足够的样本量和密集的基因型信息而不可行。总之，这些贡献将代表在ALI发病机制和预测领域的快速重大进展。 公共卫生相关性： 拟议的研究与人类健康高度相关。我们将研究改变个体对急性肺损伤（ALI）易感性的遗传因素，急性肺损伤每年影响美国超过20万例患者，死亡率为20- 25%。我们的研究将确定新的基因，有助于急性肺损伤的发病或严重程度，这些基因可能成为治疗和危险分层的新靶点。我们正在利用基因研究的力量，朝着个性化的方法来照顾危重病人。

DESCRIPTION (provided by applicant): Acute Lung Injury (ALI) is a common complication of sepsis and trauma and is associated with mortality rates 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. We will also generate an invaluable new resource for the study of genetics underlying risk for ALI that will facilitate many future studies that were previously unfeasible given the lack of adequate samples sizes and dense genotypic information. Taken together, these contributions will represent a rapid major advancement in the field of ALI pathogenesis and prediction. PUBLIC HEALTH RELEVANCE: The proposed studies are highly relevant to human health. We will investigate the genetic factors that modify an individual's susceptibility to acute lung injury (ALI), which affects more than 200,000 patients per year in the U.S. and is associated with mortality of 20-25%. Our studies will identify new genes that contribute to the onset or severity of ALI, and these genes could become new targets for treatment and risk stratification. We are using the power of genetic investigation to move towards a personalized approach to the care of critically ill patients.