Extracellular superoxide dismutase haplotypes are associated with acute lung injury and mortality

John J. Arcaroli, John E. Hokanson, Edward Abraham, Mark Geraci, James R. Murphy, Russell P. Bowler, Charles A. Dinarello, Lori Silveira, Jeff Sankoff, Daren Heyland, Paul Wischmeyer, James D. Crapo

Research output: Contribution to journalArticle

44 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)105-112
Number of pages8
JournalAmerican journal of respiratory and critical care medicine
Volume179
Issue number2
DOIs
StatePublished - Jan 15 2009

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Acute Lung Injury
Haplotypes
Superoxide Dismutase
Mortality
Linkage Disequilibrium
Lung Injury
Infection
Single Nucleotide Polymorphism
Population
Genetically Modified Animals
Genetic Linkage
Endotoxemia
Mechanical Ventilators
Oxidants
Chronic Obstructive Pulmonary Disease
Genes
Myocardial Ischemia
Pneumonia
Animal Models
Antioxidants

Keywords

  • Acute lung injury
  • EC-SOD
  • Haplotypes
  • Single nucleotide polymorphism

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Arcaroli, J. J., Hokanson, J. E., Abraham, E., Geraci, M., Murphy, J. R., Bowler, R. P., ... Crapo, J. D. (2009). Extracellular superoxide dismutase haplotypes are associated with acute lung injury and mortality. American journal of respiratory and critical care medicine, 179(2), 105-112. https://doi.org/10.1164/rccm.200710-1566OC

Extracellular superoxide dismutase haplotypes are associated with acute lung injury and mortality. / Arcaroli, John J.; Hokanson, John E.; Abraham, Edward; Geraci, Mark; Murphy, James R.; Bowler, Russell P.; Dinarello, Charles A.; Silveira, Lori; Sankoff, Jeff; Heyland, Daren; Wischmeyer, Paul; Crapo, James D.

In: American journal of respiratory and critical care medicine, Vol. 179, No. 2, 15.01.2009, p. 105-112.

Research output: Contribution to journalArticle

Arcaroli, JJ, Hokanson, JE, Abraham, E, Geraci, M, Murphy, JR, Bowler, RP, Dinarello, CA, Silveira, L, Sankoff, J, Heyland, D, Wischmeyer, P & Crapo, JD 2009, 'Extracellular superoxide dismutase haplotypes are associated with acute lung injury and mortality', American journal of respiratory and critical care medicine, vol. 179, no. 2, pp. 105-112. https://doi.org/10.1164/rccm.200710-1566OC
Arcaroli, John J. ; Hokanson, John E. ; Abraham, Edward ; Geraci, Mark ; Murphy, James R. ; Bowler, Russell P. ; Dinarello, Charles A. ; Silveira, Lori ; Sankoff, Jeff ; Heyland, Daren ; Wischmeyer, Paul ; Crapo, James D. / Extracellular superoxide dismutase haplotypes are associated with acute lung injury and mortality. In: American journal of respiratory and critical care medicine. 2009 ; Vol. 179, No. 2. pp. 105-112.
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AU - Bowler, Russell P.

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AU - Silveira, Lori

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N2 - 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.

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