title: Polymorphisms in key pulmonary inflammatory pathways and the development of acute respiratory distress syndrome.
abstract: OBJECTIVE
  Acute Respiratory Distress Syndrome (ARDS) is an important clinical and public health problem. Why some at-risk individuals develop ARDS and others do not is unclear but may be related to differences in inflammatory and cell signaling systems. The Receptor for Advanced Glycation Endproducts (RAGE) and Granulocyte-Monocyte Stimulating Factor (GM-CSF) pathways have recently been implicated in pulmonary pathophysiology; whether genetic variation within these pathways contributes to ARDS risk or outcome is unknown.
  
  
  METHODS
  We studied 842 patients from three centers in Utah and 14 non-Utah ARDS Network centers. We studied patients at risk for ARDS and patients with ARDS to determine whether Single Nucleotide Polymorphisms (SNPs) in the RAGE and GM-CSF pathways were associated with development of ARDS. We studied 29 SNPs in 5 genes within the two pathways and controlled for age, sepsis as ARDS risk factor, and severity of illness, while targeting a false discovery rate of ≤ 5%. In a secondary analysis we evaluated associations with mortality.
  
  
  RESULTS
  Of 842 patients, 690 had ARDS, and 152 were at-risk. Sepsis was the risk factor for ARDS in 250 (30%) patients. When controlling for age, APACHE III score, sepsis as risk factor, and multiple comparisons, no SNPs were significantly associated with ARDS. In a secondary analysis, only rs743564 in CSF2 approached significance with regard to mortality (OR 2.17, unadjusted p = 0.005, adjusted p = 0.15).
  
  
  CONCLUSIONS
  Candidate SNPs within 5 genes in the RAGE and GM-CSF pathways were not significantly associated with development of ARDS in this multi-centric cohort.
authors.affiliation: 1Division of Respiratory, Critical Care and Occupational Pulmonary Medicine, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Brown
authors.forename: Colin K
authors.initials: CK
authors.lastname: Grissom
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Rondina
authors.forename: John R
authors.initials: JR
authors.lastname: Hoidal
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Scholand
authors.forename: Roger K
authors.initials: RK
authors.lastname: Wolff
authors.forename: Alan H
authors.initials: AH
authors.lastname: Morris
authors.forename: Robert
authors.initials: R
authors.lastname: Paine
mesh_terms: D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D011014:Pneumonia / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics*; D012128:Respiratory Distress Syndrome / Q000235:genetics*; D012306:Risk; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics*
chemical_list: C000593871:AGER protein, human; D000067759:Receptor for Advanced Glycation End Products
keywords: GM-CSF; RAGE; acute respiratory distress syndrome; genetics