title: Distinct and replicable genetic risk factors for acute respiratory distress syndrome of pulmonary or extrapulmonary origin.
abstract: BACKGROUND
  The role of genetics in the development of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) from direct or indirect lung injury has not been specifically investigated. The aim of this study was to identify genetic variants contributing to ALI/ARDS from pulmonary or extrapulmonary causes.
  
  
  METHODS
  We conducted a multistage genetic association study. We first performed a large-scale genotyping (50K ITMAT-Broad_CARe Chip) in 1717 critically ill Caucasian patients with either pulmonary or extrapulmonary injury, to identify single nucleotide polymorphisms (SNPs) associated with the development of ARDS from direct or indirect insults to the lung. Identified SNPs (p≤0.0005) were validated in two separated populations (Stage II), with trauma (Population I; n=765) and pneumonia/pulmonary sepsis (Population II; n=838), as causes for ALI/ARDS. Genetic variants replicating their association with trauma related-ALI in Stage II were validated in a second trauma-associated ALI population (n=224, Stage III).
  
  
  RESULTS
  In Stage I, non-overlapping SNPs were significantly associated with ARDS from direct/indirect lung injury, respectively. The association between rs1190286 (POPDC3) and reduced risk of ARDS from pulmonary injury was validated in Stage II (p<0.003). SNP rs324420 (FAAH) was consistently associated with increased risk of ARDS from extrapulmonary causes in two independent ALI-trauma populations (p<0.006, Stage II; p<0.05, Stage III). Meta-analysis confirmed these associations.
  
  
  CONCLUSIONS
  Different genetic variants may influence ARDS susceptibility depending on direct versus indirect insults. Functional SNPs in POPDC3 and FAAH genes may be driving the association with direct and indirect ALI/ARDS, respectively.
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Tejera
authors.forename: Nuala J
authors.initials: NJ
authors.lastname: Meyer
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Rui
authors.initials: R
authors.lastname: Feng
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.forename: D Shane
authors.initials: DS
authors.lastname: O'Mahony
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Chau-Chyun
authors.initials: CC
authors.lastname: Sheu
authors.forename: Rihong
authors.initials: R
authors.lastname: Zhai
authors.forename: Zhaoxi
authors.initials: Z
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Su
authors.forename: Ed
authors.initials: E
authors.lastname: Bajwa
authors.forename: Amy M
authors.initials: AM
authors.lastname: Ahasic
authors.forename: Peter F
authors.initials: PF
authors.lastname: Clardy
authors.forename: Michelle N
authors.initials: MN
authors.lastname: Gong
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Frank
authors.forename: Paul N
authors.initials: PN
authors.lastname: Lanken
authors.forename: B Taylor
authors.initials: BT
authors.lastname: Thompson
authors.forename: Jason D
authors.initials: JD
authors.lastname: Christie
authors.forename: Mark M
authors.initials: MM
authors.lastname: Wurfel
authors.forename: Grant E
authors.initials: GE
authors.lastname: O'Keefe
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000581:Amidohydrolases / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012128:Respiratory Distress Syndrome / Q000235:genetics*; D012307:Risk Factors; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D015815:Cell Adhesion Molecules; D009124:Muscle Proteins; D000099252:Fatty Acid Amide Hydrolases; C498792:POPDC3 protein, human