The Next Generation of ALI Genetics: Insights into Pathophysiology

  • N. J. Meyer
  • J. D. Christie
Chapter
Part of the Annual Update in Intensive Care and Emergency Medicine 2011 book series (AUICEM, volume 1)

Abstract

The last few years have seen an explosion in the publication of gene association studies, particularly genome wide analyses, giving insight into the molecular underpinnings of disease [1, 2]. For acute lung injury (ALI), the field of genetics is just beginning to move past its infancy, from candidate gene studies to higher throughput, hypothesis-generating designs. As a phenotype, ALI can be challenging to study given the lack of available pedigrees for family-based analyses, the necessity for a severe environmental insult such as sepsis, pneumonia, trauma, or aspiration, and the heterogeneity of the populations at-risk for the syndrome and those who manifest it [3]. The search to identify genetic risk factors for ALI susceptibility or outcome draws input from molecular advances as well as from large epidemiological studies with carefully phenotyped critically ill subjects, and these efforts in tandem have recently produced exciting results. In this chapter, we will discuss the most recent developments in the effort to identify genetic risk factors contributing to ALI susceptibility or outcome, and will highlight the more novel techniques applied to this question. A glossary of genetic terms is provided (Box).

Keywords

Acute Lung Injury Acute Respiratory Distress Syndrome Respir Crit Genetic Risk Factor Candidate Gene Study 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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References

  1. 1.
    Murphy A, Chu JH, Xu M, et al (2010) Mapping of numerous disease-associated expression polymorphisms in primary peripheral blood CD4+ lymphocytes. Hum Mol Genet 19:4745–4757PubMedCrossRefGoogle Scholar
  2. 2.
    Maller J, George S, Purcell S, et al (2006) Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet 38: 1055–1059PubMedCrossRefGoogle Scholar
  3. 3.
    Meyer NJ, Garcia JG (2007) Wading into the genomic pool to unravel acute lung injury genetics. Proc Am Thorac Soc 4: 69–76PubMedCrossRefGoogle Scholar
  4. 4.
    Frazer KA, Murray SS, Schork NJ, Topol EJ (2009) Human genetic variation and its contribution to complex traits. Nat Rev Genet 10: 241–251PubMedCrossRefGoogle Scholar
  5. 5.
    Gong MN (2009) Gene association studies in acute lung injury: replication and future direction. Am J Physiol Lung Cell Mol Physiol 296: L711–712PubMedCrossRefGoogle Scholar
  6. 6.
    Coop G, Pickrell JK, Novembre J, et al (2009) The role of geography in human adaptation. PLoS Genet 5: e1000500Google Scholar
  7. 7.
    Kruglyak L, Nickerson DA (2001) Variation is the spice of life. Nat Genet 27: 234–236PubMedCrossRefGoogle Scholar
  8. 8.
    Ware LB, Matthay MA (2000) The acute respiratory distress syndrome. N Engl J Med342: 1334–1349PubMedCrossRefGoogle Scholar
  9. 9.
    Lagan AL, Melley DD, Evans TW, Quinlan GJ (2008) Pathogenesis of the systemic inflammatory syndrome and acute lung injury: role of iron mobilization and decompartmentalization. Am J Physiol Lung Cell Mol Physiol 294: L161–174PubMedCrossRefGoogle Scholar
  10. 10.
    Lin Z, Pearson C, Chinchilli V, et al (2000) Polymorphisms of human SP-A, SP-B, and SPD genes: association of SP-B Thr131Ile with ARDS. Clin Genet 58: 181–191PubMedCrossRefGoogle Scholar
  11. 11.
    Marshall RP, Webb S, Bellingan GJ, et al (2002) Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. Am J Respir Crit Care Med 166: 646–650PubMedCrossRefGoogle Scholar
  12. 12.
    Gong MN, Zhou W, Williams PL, Thompson BT, Pothier L, Christiani DC (2007) Polymorphisms in the mannose binding lectin-2 gene and acute respiratory distress syndrome. Crit Care Med 35: 48–56PubMedCrossRefGoogle Scholar
  13. 13.
    Flores C, Ma SF, Maresso K, Wade MS, Villar J, Garcia JG (2008) IL6 gene-wide haplotype is associated with susceptibility to acute lung injury. Transl Res 152: 11–17PubMedCrossRefGoogle Scholar
  14. 14.
    Sutherland AM, Walley KR, Manocha S, Russell JA (2005) The association of interleukin 6 haplotype clades with mortality in critically ill adults. Arch Intern Med 165: 75–82PubMedCrossRefGoogle Scholar
  15. 15.
    Zondervan KT, Cardon LR (2007) Designing candidate gene and genome-wide case-control association studies. Nat Protoc 2: 2492–2501PubMedCrossRefGoogle Scholar
  16. 16.
    Flores C, Pino-Yanes Mdel M, Villar J (2008) A quality assessment of genetic association studies supporting susceptibility and outcome in acute lung injury. Crit Care 12: R130PubMedCrossRefGoogle Scholar
  17. 17.
    Gao L, Barnes KC (2009) Recent advances in genetic predisposition to clinical acute lung injury. Am J Physiol Lung Cell Mol Physiol 296: L713–725PubMedCrossRefGoogle Scholar
  18. 18.
    Meyer NJ, Li M, Shah CV, et al (2009) Large scale genotyping in an African American trauma population identifies angiopoietin-2 variants associated with ALI. Am J Respir Crit Care Med 179: A3879 (abst)Google Scholar
  19. 19.
    Meyer NJ, Sheu CC, Li M, et al (2010) IL1RN polymorphism is associated with lower risk of acute lung injury in two separate at-risk populations Am J Respir Crit Care Med 181:A1023 (abst)Google Scholar
  20. 20.
    Chanock SJ, Manolio T, Boehnke M, et al (2007) Replicating genotype-phenotype associations. Nature 447: 655–660PubMedCrossRefGoogle Scholar
  21. 21.
    Glavan BJ, Holden TD, Goss CH, et al (2011) Genetic variation in the FAS gene and associations with acute lung injury. Am J Respir Crit Care Med (in press)Google Scholar
  22. 22.
    Sapru A, Hansen H, Ajayi T, et al (2009) 4G/5G polymorphism of plasminogen activator inhibitor-1 gene is associated with mortality in intensive care unit patients with severe pneumonia. Anesthesiology 110: 1086–1091PubMedCrossRefGoogle Scholar
  23. 23.
    Madach K, Aladzsity I, Szilagyi A, et al (2010) 4G/5G polymorphism of PAI-1 gene is associated with multiple organ dysfunction and septic shock in pneumonia induced severe sepsis: prospective, observational, genetic study. Crit Care 14:R79PubMedCrossRefGoogle Scholar
  24. 24.
    Christie JD, Ma SF, Aplenc R, et al (2008) Variation in the myosin light chain kinase gene is associated with development of acute lung injury after major trauma. Crit Care Med 36: 2794–2800PubMedCrossRefGoogle Scholar
  25. 25.
    Arcaroli JJ, Hokanson JE, Abraham E, et al (2009) Extracellular superoxide dismutase haplotypes are associated with acute lung injury and mortality. Am J Respir Crit Care Med 179: 105–112PubMedCrossRefGoogle Scholar
  26. 26.
    Gong MN, Thompson BT, Williams PL, et al (2006) Interleukin-10 polymorphism in position-1082 and acute respiratory distress syndrome. Eur Respir J 27: 674–681PubMedCrossRefGoogle Scholar
  27. 27.
    Medford AR, Keen LJ, Bidwell JL, Millar AB (2005) Vascular endothelial growth factor gene polymorphism and acute respiratory distress syndrome. Thorax 60: 244–248PubMedCrossRefGoogle Scholar
  28. 28.
    Su L, Zhai R, Sheu CC, et al (2009) Genetic variants in the angiopoietin-2 gene are associated with increased risk of ARDS. Intensive Care Med 35: 1024–1030PubMedCrossRefGoogle Scholar
  29. 29.
    dos Santos CC, Okutani D, Hu P, et al (2008) Differential gene profiling in acute lung injury identifies injury-specific gene expression. Crit Care Med 36: 855–865PubMedCrossRefGoogle Scholar
  30. 30.
    Kanehisa M, Goto S (2000) KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28: 27–30PubMedCrossRefGoogle Scholar
  31. 31.
    Ashburner M, Ball CA, Blake JA, et al (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25: 25–29PubMedCrossRefGoogle Scholar
  32. 32.
    Huang DW, Sherman BT, Lempicki RA (2008) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protocols 4: 44–57CrossRefGoogle Scholar
  33. 33.
    Grigoryev DN, Ma SF, Irizarry RA, Ye SQ, Quackenbush J, Garcia JG (2004) Orthologous gene-expression profiling in multi-species models: search for candidate genes. Genome Biol 5: R34PubMedCrossRefGoogle Scholar
  34. 34.
    Ye SQ, Simon BA, Maloney JP, et al (2005) Pre-B-cell colony-enhancing factor as a potential novel biomarker in acute lung injury. Am J Respir Crit Care Med 171: 361–370PubMedCrossRefGoogle Scholar
  35. 35.
    Leikauf GD, Pope-Varsalona H, Concel VJ, et al (2010) Functional genomics of chlorine-induced acute lung injury in mice. Proc Am Thorac Soc 7: 294–296PubMedCrossRefGoogle Scholar
  36. 36.
    Wang Z, Beach D, Su L, Zhai R, Christiani DC (2008) A genome-wide expression analysis in blood identifies pre-elafin as a biomarker in ARDS. Am J Respir Cell Mol Biol 38: 724–732PubMedCrossRefGoogle Scholar
  37. 37.
    Howrylak JA, Dolinay T, Lucht L, et al (2009) Discovery of the gene signature for acute lung injury in patients with sepsis. Physiol Genomics 37: 133–139PubMedCrossRefGoogle Scholar
  38. 38.
    Feero WG, Guttmacher AE, Collins FS (2010) Genomic medicine—an updated primer. N Engl J Med 362: 2001–2011PubMedCrossRefGoogle Scholar
  39. 39.
    Frazer KA, Ballinger DG, Cox DR, et al (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449: 851–861PubMedCrossRefGoogle Scholar
  40. 40.
    McClellan J, King MC (2010) Genetic heterogeneity in human disease. Cell 141: 210–217PubMedCrossRefGoogle Scholar
  41. 41.
    McCarthy MI, Abecasis GR, Cardon LR, et al (2008) Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet 9: 356–369PubMedCrossRefGoogle Scholar
  42. 42.
    Keating BJ, Tischfield S, Murray SS, et al (2008) Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies. PLoS ONE 3: e3583PubMedCrossRefGoogle Scholar
  43. 43.
    Christie JD, Wurfel MM, O’Keefe GE, et al (2010) Genome wide association (gwa) identifies functional susceptibility loci for acute lung injury Am J Respir Crit Care Med 181: A1025. (abst)Google Scholar
  44. 44.
    Wurfel MM, Christiani D, Christie JD, et al (2009) Genetic risks for ALI in the ARDSnet and iSPAAR consortium. Grant award from the National Heart Lung and Blood Institute of the National Institutes of HealthGoogle Scholar
  45. 45.
    Manolio TA, Collins FS, Cox NJ, et al (2009) Finding the missing heritability of complex diseases. Nature 461: 747–753PubMedCrossRefGoogle Scholar
  46. 46.
    Ng PC, Kirkness EF (2010) Whole genome sequencing. Methods Mol Biol 628: 215–226PubMedCrossRefGoogle Scholar
  47. 47.
    Ng SB, Buckingham KJ, Lee C, et al (2010) Exome sequencing identifies the cause of a mendelian disorder. Nat Genet 42: 30–35PubMedCrossRefGoogle Scholar
  48. 48.
    Cookson W, Liang L, Abecasis G, Moffatt M, Lathrop M (2009) Mapping complex disease traits with global gene expression. Nat Rev Genet 10: 184–194PubMedCrossRefGoogle Scholar
  49. 49.
    Wurfel MM, Gordon AC, Holden TD, et al (2008) Toll-like receptor 1 polymorphisms affect innate immune responses and outcomes in sepsis. Am J Respir Crit Care Med 178:710–720PubMedCrossRefGoogle Scholar
  50. 50.
    Dixon AL, Liang L, Moffatt MF, et al (2007) A genome-wide association study of global gene expression. Nat Genet 39: 1202–1207PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media LLC 2011

Authors and Affiliations

  • N. J. Meyer
    • 1
  • J. D. Christie
    • 2
  1. 1.Department of Medicine, Pulmonary, Allergy, and Critical Care DivisionUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  2. 2.Department of Medicine, Pulmonary, Allergy and Critical Care DivisionUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

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