1. Extracellular superoxide dismutase haplotypes are associated with acute lung injury and mortality.
- Author
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Arcaroli JJ, Hokanson JE, Abraham E, Geraci M, Murphy JR, Bowler RP, Dinarello CA, Silveira L, Sankoff J, Heyland D, Wischmeyer P, and Crapo JD
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers metabolism, Case-Control Studies, Colorado epidemiology, Female, Genetic Variation, Genome, Human, Humans, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, Survival Analysis, White People statistics & numerical data, Acute Lung Injury genetics, Acute Lung Injury mortality, Haplotypes, Superoxide Dismutase genetics
- Abstract
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.
- Published
- 2009
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