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Original article
Distinct and replicable genetic risk factors for acute respiratory distress syndrome of pulmonary or extrapulmonary origin
  1. Paula Tejera1,
  2. Nuala J Meyer2,
  3. Feng Chen3,
  4. Rui Feng4,
  5. Yang Zhao1,
  6. D Shane O'Mahony5,
  7. Lin Li1,
  8. Chau-Chyun Sheu6,
  9. Rihong Zhai1,
  10. Zhaoxi Wang1,
  11. Li Su1,
  12. Ed Bajwa7,
  13. Amy M Ahasic8,
  14. Peter F Clardy9,
  15. Michelle N Gong10,
  16. Angela J Frank7,
  17. Paul N Lanken2,
  18. B Taylor Thompson7,
  19. Jason D Christie2,4,
  20. Mark M Wurfel5,
  21. Grant E O'Keefe5,
  22. David C Christiani1,7
  1. 1Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA
  2. 2Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
  3. 3Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
  4. 4Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
  5. 5Division of Pulmonary and Critical Care Medicine, Department of Medicine, Harborview Medical Center, University of Washington, Seattle, Washington, USA
  6. 6Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
  7. 7Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
  8. 8Section of Pulmonary and Critical Care Medicine, Department of Medicine, The Anlyan Center, Yale University School of Medicine, New Haven, Connecticut, USA
  9. 9Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, Massachusetts, USA
  10. 10Division of Critical Care Medicine, Department of Medicine, Montefiore Medical Center, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA
  1. Correspondence to Dr David C Christiani, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Room I-1401, Boston, MA 02115, USA; dchris{at}hsph.harvard.edu

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.

  • Genetic epidemiology
  • Complex traits
  • Respiratory Medicine

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