title: IL1RN coding variant is associated with lower risk of acute respiratory distress syndrome and increased plasma IL-1 receptor antagonist.
abstract: BACKGROUND
  Acute respiratory distress syndrome (ARDS) behaves as a complex genetic trait, yet knowledge of genetic susceptibility factors remains incomplete.
  
  
  OBJECTIVE
  To identify genetic risk variants for ARDS using large scale genotyping.
  
  
  METHODS
  A multistage genetic association study was conducted of three critically ill populations phenotyped for ARDS. Stage I, a trauma cohort study (n = 224), was genotyped with a 50K gene-centric single-nucleotide polymorphism (SNP) array. We tested SNPs associated with ARDS at P < 5 × 10(-4) for replication in stage II, a trauma case-control population (n = 778). SNPs replicating their association in stage II (P < 0.005) were tested in a stage III nested case-control population of mixed subjects in the intensive care unit (n = 2,063). Logistic regression was used to adjust for potential clinical confounders. We performed ELISA to test for an association between ARDS-associated genotype and plasma protein levels.
  
  
  RESULTS
  A total of 12 SNPs met the stage I threshold for an association with ARDS. rs315952 in the IL1RN gene encoding IL-1 receptor antagonist (IL1RA) replicated its association with reduced ARDS risk in stages II (P < 0.004) and III (P < 0.02), and was robust to clinical adjustment (combined odds ratio = 0.81; P = 4.2 × 10(-5)). Plasma IL1RA level was associated with rs315952C in a subset of critically ill subjects. The effect of rs315952 was independent from the tandem repeat variant in IL1RN.
  
  
  CONCLUSIONS
  The IL1RN SNP rs315952C is associated with decreased risk of ARDS in three populations with heterogeneous ARDS risk factors, and with increased plasma IL1RA response. IL1RA may attenuate ARDS risk.
authors: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. nuala.meyer@uphs.upenn.edu
authors: Nuala J
authors: NJ
authors: Meyer
authors: Rui
authors: R
authors: Feng
authors: Mingyao
authors: M
authors: Li
authors: Yang
authors: Y
authors: Zhao
authors: Chau-Chyun
authors: CC
authors: Sheu
authors: Paula
authors: P
authors: Tejera
authors: Robert
authors: R
authors: Gallop
authors: Scarlett
authors: S
authors: Bellamy
authors: Melanie
authors: M
authors: Rushefski
authors: Paul N
authors: PN
authors: Lanken
authors: Richard
authors: R
authors: Aplenc
authors: Grant E
authors: GE
authors: O'Keefe
authors: Mark M
authors: MM
authors: Wurfel
authors: David C
authors: DC
authors: Christiani
authors: Jason D
authors: JD
authors: Christie
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007362:Intensive Care Units; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics*; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D012306:Risk; D012307:Risk Factors; D012720:Severity of Illness Index
chemical_list: D017472:Receptors, Interleukin-1