Primary graft dysfunction (PGD) is severe acute lung injury occurring in the days after lung transplantation, characterized by diffuse pulmonary edema and profound hypoxemia. PGD has a major impact on outcomes following lung transplantation, markedly increasing morbidity, mortality, and cost. Thus, reduction in the incidence of PGD would dramatically improve clinical and economic outcomes following lung transplantation. In addition, concern about PGD following lung transplantation is a main reason why more lung donors are not considered suitable, therefore the ability to predict PGD could increase the number of transplants performed. Recent work by our group suggests that inherent donor and recipient characteristics play an important role in determining risk of PGD. In addition, like many other forms of acute lung injury and ischemia reperfusion injury, there is evidence that oxidant stress pathways play an important role in the process leading to PGD. Specifically, we hypothesize that genetic variation in regulators of reactive oxygen species (ROS) production and detoxification in donors and recipients influences the risk of PGD following lung transplantation. This study expands our established multicenter cohort study infrastructure, including prospective clinical data collection and sequential blood sample collection, to achieve the following specific aims: 1) Determine the association of candidate oxidant stress regulatory genes in recipients with development of PGD following lung transplantation;and 2) Determine the association of candidate oxidant stress regulatory genes in donors with development of PGD following lung transplantation. To achieve these aims, we plan a multicentered cohort study including over 2200 subjects at 9 different centers throughout the U.S. Analyses will include both individual candidate functional SNP associations as well as haplotype associations with PGD, adjustment for confounding clinical variables;testing interactions of candidate genes and haplotypes with clinical variables;determination of gene/gene interactions;and evaluation of genotypes as clinical predictors of PGD The results of the current molecular epidemiological proposal will directly lead to better understanding of the causes of PGD;suggest further clinical and laboratory investigations aimed at understanding discovered genetic associations;increase the ability to predict PGD in donors and recipients to stratify risk;identify low- risk procedures for liberalization of traditional donor criteria;and suggest prevention trials of PGD in specific at-risk populations using pharmacogenomic approaches.
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