Genetics of Acute Respiratory Distress Syndrome

Abstract

The acute respiratory distress syndrome (ARDS), a diffuse lung inflammation leading to an acute hypoxemia, is a complex syndrome induced by a systemic inflammatory response commonly caused by severe infections or trauma. Despite the heterogeneous mechanisms underlying disease causality, genetic risk factors involved in ARDS susceptibility and outcomes are being identified. However, a full characterisation of the genetic architecture of this syndrome remains to be completed. Novel ‘omics’ tools have the promise for recognising ARDS subtypes, which will allow the identification of novel risk factors that will translate into individualised patient management and treatments, potentially leading to better individual prognosis. An important direction for future research is to encourage the use of large and well‐characterised samples, ensure that patients of diverse ancestry are included in genetic studies and establish the clinical utility of risk variants identified for prevention, therapy or risk stratification.

Key Concepts

  • Acute respiratory distress syndrome (ARDS) remains a major cause of death in adult intensive care units, with an overall hospital mortality of about 40%.
  • Clinical trials and animal models indicate that mechanical ventilation using low tidal volumes remains one of the few proven interventions to reduce ARDS mortality.
  • ARDS is a complex syndrome with a large phenotypic variation.
  • Association studies have been widely used to find genetic variants involved in ARDS susceptibility and outcome, and several genes have been associated with ARDS, including IL6, IL10, VEGFA, ACE, MBL2, IL1RN and NAMPT.

Keywords: acute lung injury; diffuse alveolar damage; ventilator‐induced lung injury; polymorphism; SNP; association studies; GWAS; exome

Figure 1. Schematic representation of an alveolus and a pulmonary capillary depicting the potential links between the ARDS susceptibility genes and key biological processes involved in the pathogenesis. In bold, genes with evidence of association in at least four study samples. Gene symbols correspond to the acronyms provided by the NCBI website.
close

References

Acosta‐Herrera M, Pino‐Yanes M, Perez‐Mendez L, et al. (2014) Assessing the quality of studies supporting genetic susceptibility and outcomes of ARDS. Frontiers in Genetics 5: 20.

Acosta‐Herrera M, Lorenzo‐Diaz F, Pino‐Yanes M, et al. (2015) Lung transcriptomics during protective ventilatory support in sepsis‐induced acute lung injury. PLoS One 10 (7): e0132296.

Altemeier WA, Matute‐Bello G, Frevert CW, et al. (2004) Mechanical ventilation with moderate tidal volumes synergistically increases lung cytokine response to systemic endotoxin. American Journal of Physiology. Lung Cellular and Molecular Physiology 287 (3): L533–L542.

Altemeier WA, Matute‐Bello G, Gharib SA, et al. (2005) Modulation of lipopolysaccharide‐induced gene transcription and promotion of lung injury by mechanical ventilation. Journal of Immunology 175 (5): 3369–3376.

Bernard GR, Artigas A, Brigham KL, et al. (1994) The American‐European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. American Journal of Respiratory and Critical Care Medicine 149 (3 Pt 1): 818–824.

Bersten AD, Edibam C, Hunt T, et al. (2002) Incidence and mortality of acute lung injury and the acute respiratory distress syndrome in three Australian States. American Journal of Respiratory and Critical Care Medicine 165 (4): 443–448.

Buregeya E, Fowler RA, Talmor DS, et al. (2014) Acute respiratory distress syndrome in the global context. Global Heart 9 (3): 289–295.

Carlucci M, Graf N, Simmons JQ, et al. (2014) Effective management of ARDS. Nurse Practitioner 39 (12): 35–40.

Caser EB, Zandonade E, Pereira E, et al. (2014) Impact of distinct definitions of acute lung injury on its incidence and outcomes in Brazilian ICUs: prospective evaluation of 7,133 patients. Critical Care Medicine 42 (3): 574–582.

Clark MF and Baudouin SV (2006) A systematic review of the quality of genetic association studies in human sepsis. Intensive Care Medicine 32 (11): 1706–1712.

Copland IB, Kavanagh BP, Engelberts D, et al. (2003) Early changes in lung gene expression due to high tidal volume. American Journal of Respiratory and Critical Care Medicine 168 (9): 1051–1059.

Chanock SJ, Manolio T, Boehnke M, et al. (2007) Replicating genotype‐phenotype associations. Nature 447 (7145): 655–660.

Christie JD, Wurfel MM, Feng R, et al. (2012) Genome wide association identifies PPFIA1 as a candidate gene for acute lung injury risk following major trauma. PLoS One 7 (1): e28268.

Chung CM, Lin TH, Chen JW, et al. (2011) A genome‐wide association study reveals a quantitative trait locus of adiponectin on CDH13 that predicts cardiometabolic outcomes. Diabetes 60 (9): 2417–2423.

Debette S, Visvikis‐Siest S, Chen MH, et al. (2011) Identification of cis‐ and trans‐acting genetic variants explaining up to half the variation in circulating vascular endothelial growth factor levels. Circulation Research 109 (5): 554–563.

Dolinay T, Kaminski N, Felgendreher M, et al. (2006) Gene expression profiling of target genes in ventilator‐induced lung injury. Physiological Genomics 26 (1): 68–75.

Erickson SE, Martin GS, Davis JL, et al. (2009) Recent trends in acute lung injury mortality: 1996–2005. Critical Care Medicine 37 (5): 1574–1579.

Flores C, Pino‐Yanes Mdel M and Villar J (2008) A quality assessment of genetic association studies supporting susceptibility and outcome in acute lung injury. Critical Care 12 (5): R130.

Flores C, Pino‐Yanes MM, Casula M, et al. (2010) Genetics of acute lung injury: past, present and future. Minerva Anestesiologica 76 (10): 860–864.

Gajic O, Dabbagh O, Park PK, et al. (2011) Early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study. American Journal of Respiratory and Critical Care Medicine 183 (4): 462–470.

Gharib SA, Liles WC, Matute‐Bello G, et al. (2006) Computational identification of key biological modules and transcription factors in acute lung injury. American Journal of Respiratory and Critical Care Medicine 173 (6): 653–658.

Goh G and Choi M (2012) Application of whole exome sequencing to identify disease‐causing variants in inherited human diseases. Genomics & Informatics 10 (4): 214–219.

Grigoryev DN, Ma SF, Irizarry RA, et al. (2004) Orthologous gene‐expression profiling in multi‐species models: search for candidate genes. Genome Biology 5 (5): R34.

Hughes M, MacKirdy FN, Ross J, et al. (2003) Acute respiratory distress syndrome: an audit of incidence and outcome in Scottish intensive care units. Anaesthesia 58 (9): 838–845.

Kangelaris KN, Sapru A, Calfee CS, et al. (2012) The association between a DARC gene polymorphism and clinical outcomes in African American patients with acute lung injury. Chest 141 (5): 1160–1169.

Lee S, Emond MJ, Bamshad MJ, et al. (2012) Optimal unified approach for rare‐variant association testing with application to small‐sample case‐control whole‐exome sequencing studies. American Journal of Human Genetics 91 (2): 224–237.

Leikauf GD, McDowell SA, Wesselkamper SC, et al. (2002) Acute lung injury: functional genomics and genetic susceptibility. Chest 121 (3 Suppl): 70S–75S.

Li G, Malinchoc M, Cartin‐Ceba R, et al. (2011) Eight‐year trend of acute respiratory distress syndrome: a population‐based study in Olmsted County, Minnesota. American Journal of Respiratory and Critical Care Medicine 183 (1): 59–66.

Luhr OR, Antonsen K, Karlsson M, et al. (1999) Incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland. American Journal of Respiratory and Critical Care Medicine 159 (6): 1849–1861.

Martin TR, Rubenfeld GD, Ruzinski JT, et al. (1997) Relationship between soluble CD14, lipopolysaccharide binding protein, and the alveolar inflammatory response in patients with acute respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine 155 (3): 937–944.

Medford AR, Godinho SI, Keen LJ, et al. (2009) Relationship between vascular endothelial growth factor + 936 genotype and plasma/epithelial lining fluid vascular endothelial growth factor protein levels in patients with and at risk for ARDS. Chest 136 (2): 457–464.

Meduri GU, Headley S, Kohler G, et al. (1995) Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL‐1 beta and IL‐6 levels are consistent and efficient predictors of outcome over time. Chest 107 (4): 1062–1073.

Meyer NJ, Feng R, Li M, et al. (2013) IL1RN coding variant is associated with lower risk of acute respiratory distress syndrome and increased plasma IL‐1 receptor antagonist. American Journal of Respiratory and Critical Care Medicine 187 (9): 950–959.

Moss M, Bucher B, Moore FA, et al. (1996) The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults. JAMA 275 (1): 50–54.

Moss M and Mannino DM (2002) Race and gender differences in acute respiratory distress syndrome deaths in the United States: an analysis of multiple‐cause mortality data (1979–1996). Critical Care Medicine 30 (8): 1679–1685.

Nicholls J and Peiris M (2005) Good ACE, bad ACE do battle in lung injury, SARS. Nature Medicine 11 (8): 821–822.

Petersen L, Andersen PK and Sorensen TI (2010) Genetic influences on incidence and case‐fatality of infectious disease. PLoS One 5 (5): e10603.

Ranieri VM, Rubenfeld GD, Thompson BT, et al. (2012) Acute respiratory distress syndrome: the Berlin Definition. JAMA 307 (23): 2526–2533.

Risch N and Merikangas K (1996) The future of genetic studies of complex human diseases. Science 273 (5281): 1516–1517.

Shortt K, Chaudhary S, Grigoryev D, et al. (2014) Identification of novel single nucleotide polymorphisms associated with acute respiratory distress syndrome by exome‐seq. PLoS One 9 (11): e111953.

Spragg RG, Bernard GR, Checkley W, et al. (2010) Beyond mortality: future clinical research in acute lung injury. American Journal of Respiratory and Critical Care Medicine 181 (10): 1121–1127.

Suchyta MR, Clemmer TP, Elliott CG, et al. (1997) Increased mortality of older patients with acute respiratory distress syndrome. Chest 111 (5): 1334–1339.

The Acute Respiratory Distress Syndrome Network (2000) Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. New England Journal of Medicine 342 (18): 1301–1308.

Valta P, Uusaro A, Nunes S, et al. (1999) Acute respiratory distress syndrome: frequency, clinical course, and costs of care. Critical Care Medicine 27 (11): 2367–2374.

Villar J, Flores C and Mendez‐Alvarez S (2003) Genetic susceptibility to acute lung injury. Critical Care Medicine 31 (4 Suppl): S272–S275.

Villar J, Blanco J, Anon JM, et al. (2011a) The ALIEN study: incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation. Intensive Care Medicine 37 (12): 1932–1941.

Villar J, Blanco J, Zhang H, et al. (2011b) Ventilator‐induced lung injury and sepsis: two sides of the same coin? Minerva Anestesiologica 77 (6): 647–653.

Ware LB and Matthay MA (2001) Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine 163 (6): 1376–1383.

Ware LB (2006) Pathophysiology of acute lung injury and the acute respiratory distress syndrome. Seminars in Respiratory and Critical Care Medicine 27 (4): 337–349.

Wurfel MM (2007) Microarray‐based analysis of ventilator‐induced lung injury. Proceedings of the American Thoracic Society 4 (1): 77–84.

Yang S, Cao S, Li J, et al. (2011) Association between vascular endothelial growth factor + 936 genotype and acute respiratory distress syndrome in a Chinese population. Genetic Testing and Molecular Biomarkers 15 (10): 737–740.

Ye SQ, Simon BA, Maloney JP, et al. (2005a) Pre‐B‐cell colony‐enhancing factor as a potential novel biomarker in acute lung injury. American Journal of Respiratory and Critical Care Medicine 171 (4): 361–370.

Ye SQ, Zhang LQ, Adyshev D, et al. (2005b) Pre‐B‐cell‐colony‐enhancing factor is critically involved in thrombin‐induced lung endothelial cell barrier dysregulation. Microvascular Research 70 (3): 142–151.

Zhai R, Gong MN, Zhou W, et al. (2007) Genotypes and haplotypes of the VEGF gene are associated with higher mortality and lower VEGF plasma levels in patients with ARDS. Thorax 62 (8): 718–722.

Zhou T, Garcia JG and Zhang W (2011) Integrating microRNAs into a system biology approach to acute lung injury. Translational Research 157 (4): 180–190.

Further Reading

Flores C, Ma SF, Maresso K, et al. (2006) Genomics of acute lung injury. Seminars in Respiratory and Critical Care Medicine 27 (4): 389–395.

Meyer NJ (2013) Future clinical applications of genomics for acute respiratory distress syndrome. Lancet Respiratory Medicine 1 (10): 793–803.

Meyer NJ (2014) Beyond single‐nucleotide polymorphisms: genetics, genomics, and other ‘omic’ approaches to acute respiratory distress syndrome. Clinics in Chest Medicine 35 (4): 673–684.

Rubenfeld GD, Caldwell E, Peabody E, et al. (2005) Incidence and outcomes of acute lung injury. New England Journal of Medicine 353 (16): 1685–1693.

Web links

The 1000 Genomes Project: This website provides detailed information of the project, sampled populations and methods, as well as tools to browse the genetic variation across ethnicities. http://www.1000genomes.org.

NCBI: This website provides the official full names of all described genes as well as additional information related to each of them. http://www.ncbi.nlm.nih.gov/gene.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Guillén‐Guío, Beatriz, Acosta‐Herrera, Marialbert, Villar, Jesús, and Flores, Carlos(Apr 2016) Genetics of Acute Respiratory Distress Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026533]