Association between urokinase haplotypes and outcome from infection-associated acute lung injury

Objective Alterations in coagulation, including elevated pulmonary and systemic concentrations of urokinase, are frequent in patients with acute lung injury (ALI). Urokinase potentiates neutrophil activation and contributes to the severity of pulmonary injury in preclinical models of ALI. The objective of this study was to examine associations between polymorphisms and haplotypes of urokinase with risk for and outcomes from ALI. Design Prospective cohorts of healthy European-American adults and those with infection-associated ALI. Setting Academic medical centers participating in NIH funded studies of low tidal volume ventilation for ALI. Patients Controls were 175 healthy European-American subjects. Patients were 252 individuals with infection-associated ALI, prospectively followed for 60 days for mortality. Interventions Genetic polymorphisms and haplotypes in the urokinase gene were determined. Measurements and main results Six polymorphisms, rs1916341, rs2227562, rs2227564, rs2227566, rs2227571, and rs4065, defining 98% of all urokinase haplotypes, were analyzed. There were no statistically significant associations between any single urokinase polymorphism or haplotype and risk for developing ALI. In contrast, there was a statistically significant relationship between the CGCCCC haplotype and both 60-day mortality and ventilator-free days that remained present in a multivariate analysis controlling for age and sex ( p = 0.033 for 60-day mortality and < 0.001 for ventilator-free days). Conclusions These results identify a specific urokinase haplotype as a genetic risk factor for higher mortality and more severe clinical outcome in patients with infection-associated ALI.