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Extracellular Superoxide Dismutase Haplotypes Are Associated with Acute Lung Injury and Mortality

¹ Division of Pulmonary Sciences and Critical Care Medicine, ² Department of Preventive Medicine and Biometrics, ⁶ Division of Infectious Disease, and ⁷ Division of Emergency Medicine, Department of Surgery, University of Colorado at Denver, and Health Sciences Center, Denver, Colorado; ³ Department of Medicine, University of Alabama, Birmingham, Alabama; ⁴ Department of Biostatistics, ⁵ Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado; and ⁸ Kingston General Hospital, Kingston, Ontario, Canada

Correspondence and requests for reprints should be addressed to James Crapo, M.D., Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206. E-mail: crapoj{at}njc.org

Rationale: Extracellular superoxide dismutase (EC-SOD) is a potent antioxidant that plays an important role in controlling oxidant-mediated stress and inflammation. High levels of EC-SOD are found in the lung. Acute lung injury (ALI) frequently occurs in patients with infection, and levels of EC-SOD have been shown to modulate severity of lung injury in transgenic animal models of endotoxemia-induced ALI. An R213G single nucleotide polymorphism (SNP) has been shown to alter levels of EC-SOD and patient outcomes in chronic obstructive pulmonary disease (COPD) and ischemic heart disease.

Objectives: To determine genetic variation in the promoter and EC-SOD gene and to examine whether EC-SOD haplotype blocks are associated with clinical outcomes.

Methods: We sequenced the EC-SOD promoter and gene to determine genetic variation and linkage disequilibrium (LD) patterns in a European American population. Two separate patient populations with infection-associated ALI were also evaluated to determine whether EC-SOD haplotypes were associated with clinical outcomes.

Measurements and Main Results: Sequencing resulted in the identification of 28 SNPs with relatively strong LD and 1 block consisting of 4691-5321-5360-5955-5982. This specific block was shown to be protective in two separate patient populations with infection associated ALI. In particular, patients with a GCCT haplotype had a reduced risk of time on the ventilator and mortality.

Conclusions: These results indicate that a GCCT haplotype may reduce inflammation in the lung, thereby decreasing the severity of lung injury and ultimately protecting patients from mortality associated with infection-induced ALI.

Key Words: EC-SOD • haplotypes • acute lung injury • single nucleotide polymorphism

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Extracellular superoxide dismutase (EC-SOD) is a potent antioxidant that plays an important role in protecting the lung against oxidant-mediated stress and inflammation. A R213G single nucleotide polymorphism in the EC-SOD gene has been shown to reduce susceptibility to chronic obstructive pulmonary disease. What This Study Adds to the Field These results indicate that a GCCT haplotype of EC-SOD may reduce inflammation in the lung, thereby decreasing the severity of lung injury and ultimately protecting patients from mortality associated with infection-induced ALI.

 

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Extracellular Superoxide Dismutase Haplotypes and Acute Lung Injury: Reading into the Genome to Understand Mortality?

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