Intensive Care Medicine

, Volume 35, Issue 6, pp 1024–1030 | Cite as

Genetic variants in the angiopoietin-2 gene are associated with increased risk of ARDS

  • Li Su
  • Rihong Zhai
  • Chau-Chyun Sheu
  • Diana C. Gallagher
  • Michelle N. Gong
  • Paula Tejera
  • B. Taylor Thompson
  • David C. ChristianiEmail author



Angiopoietin-2 (Ang-2) is a potent regulator of vascular permeability and inflammation in acute lung injury and acute respiratory distress syndrome (ARDS). Genetic variants in the Ang-2 gene may lead to altered activities of Ang-2 (or ANGPT2) gene. The aim of this study was to assess if genetic variants of Ang-2 are associated with the risk of ARDS.


Unmatched, case-control study nested within a prospectively enrolled cohort.


Intensive care units (ICU) of an academic medical center.


About 1,529 critically ill patients with risk factors for ARDS consecutively admitted to the ICUs from 1999 to 2006. Cases were 449 patients who developed ARDS and controls were 1,080 subjects who did not developed ARDS.



Measurements and results

Nine tagging SNPs (tSNPs) spanning the entire Ang-2 gene were genotyped in all patients. The results were analyzed using logistic regression models, adjusting for covariates. The variant T allele of one tSNP (rs2515475) was significantly associated with increased risk of ARDS (ORadjusted = 1.28; P = 0.042). This association was stronger in subjects with extrapulmonary injuries (ORadjusted = 1.79; P = 0.004). Haplotype TT in block 2 containing the T allele of the rs2515475 was also significantly associated with higher risk of ARDS (ORadjusted = 1.42; = 0.009), particularly in subjects with extrapulmonary injuries (ORadjusted = 1.90; P = 0.004).


Common genetic variation in the Ang-2 gene may be associated with increased risk of ARDS, especially among patients with extrapulmonary injuries.


Angiopoietin-2 Genetic susceptibility ARDS Tagging single nucleotide polymorphism Haplotype Molecular epidemiology 



This research was supported by grants from National Institute of Health (HL60710, ES00002) and Flight Attendant Medical Research Institute (062459-YCSA). The authors would like to thank Weiling Zhang, Kelly McCoy, Thomas McCabe, Julia Shin, and Hanae Fujii-Rios for patient recruitment; Andrea Shafer and Starr Sumpter for research support; Maureen Convery for laboratory expertise; Janna Frelich for data management; and the patients and staff of ICUs at Massachusetts General Hospital.

Supplementary material

134_2009_1413_MOESM1_ESM.doc (42 kb)
Supplemental Table (DOC 41 kb)


  1. 1.
    Piantadosi CA, Schwartz DA (2004) The acute respiratory distress syndrome. Ann Intern Med 141:460–470PubMedGoogle Scholar
  2. 2.
    Ware LB, Matthay MA (2000) The acute respiratory distress syndrome. N Engl J Med 342:1334–1349PubMedCrossRefGoogle Scholar
  3. 3.
    Andrews P, Azoulay E, Antonelli M, Brochard L, Brun-Buisson C, De Backer D, Dobb G, Fagon JY, Gerlach H, Groeneveld J, Macrae D, Mancebo J, Metnitz P, Nava S, Pugin J, Pinsky M, Radermacher P, Richard C (2007) Year in review in intensive care medicine, 2006. II. Infections and sepsis, haemodynamics, elderly, invasive and noninvasive mechanical ventilation, weaning, ARDS. Intensive Care Med 33:214–229PubMedCrossRefGoogle Scholar
  4. 4.
    Orfanos SE, Mavrommati I, Korovesi I, Roussos C (2004) Pulmonary endothelium in acute lung injury: from basic science to the critically ill. Intensive Care Med 30:1702–1714PubMedCrossRefGoogle Scholar
  5. 5.
    Maniatis NA, Orfanos SE (2008) The endothelium in acute lung injury/acute respiratory distress syndrome. Curr Opin Crit Care 14:22–30PubMedCrossRefGoogle Scholar
  6. 6.
    McDonald DM (2001) Angiogenesis and remodeling of airway vasculature in chronic inflammation. Am J Respir Crit Care Med 164:S39–S45PubMedGoogle Scholar
  7. 7.
    Koh GY, Kim I, Kwak HJ, Yun MJ, Leem JC (2002) Biomedical significance of endothelial cell specific growth factor, angiopoietin. Exp Mol Med 34:1–11PubMedGoogle Scholar
  8. 8.
    Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55–60PubMedCrossRefGoogle Scholar
  9. 9.
    Fiedler U, Augustin HG (2006) Angiopoietins: a link between angiogenesis and inflammation. Trends Immunol 27:552–558PubMedCrossRefGoogle Scholar
  10. 10.
    Roviezzo F, Tsigkos S, Kotanidou A, Bucci M, Brancaleone V, Cirino G, Papapetropoulos A (2005) Angiopoietin-2 causes inflammation in vivo by promoting vascular leakage. J Pharmacol Exp Ther 314:738–744PubMedCrossRefGoogle Scholar
  11. 11.
    Rondaij MG, Bierings R, Kragt A, van Mourik JA, Voorberg J (2006) Dynamics and plasticity of Weibel-Palade bodies in endothelial cells. Arterioscler Thromb Vasc Biol 26:1002–1007PubMedCrossRefGoogle Scholar
  12. 12.
    Bhandari V, Choo-Wing R, Lee CG, Zhu Z, Nedrelow JH, Chupp GL, Zhang X, Matthay MA, Ware LB, Homer RJ, Lee PJ, Geick A, de Fougerolles AR, Elias JA (2006) Hyperoxia causes angiopoietin 2-mediated acute lung injury and necrotic cell death. Nat Med 12:1286–1293PubMedCrossRefGoogle Scholar
  13. 13.
    Parikh SM, Mammoto T, Schultz A, Yuan HT, Christiani D, Karumanchi SA, Sukhatme VP (2006) Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans. PLoS Med 3:e46PubMedCrossRefGoogle Scholar
  14. 14.
    Orfanos SE, Kotanidou A, Glynos C, Athanasiou C, Tsigkos S, Dimopoulou I, Sotiropoulou C, Zakynthinos S, Armaganidis A, Papapetropoulos A, Roussos C (2007) Angiopoietin-2 is increased in severe sepsis: correlation with inflammatory mediators. Crit Care Med 35:199–206PubMedCrossRefGoogle Scholar
  15. 15.
    Gallagher DC, Parikh SM, Balonov K, Miller A, Gautam S, Talmor D, Sukhatme VP (2008) Circulating angiopoietin 2 correlates with mortality in a surgical population with acute lung injury/adult respiratory distress syndrome. Shock 29:656–661PubMedCrossRefGoogle Scholar
  16. 16.
    Ward EG, Grosios K, Markham AF, Jones PF (2001) Genomic structures of the human angiopoietins show polymorphism in angiopoietin-2. Cytogenet Cell Genet 94:147–154PubMedCrossRefGoogle Scholar
  17. 17.
    International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437:1299–1320CrossRefGoogle Scholar
  18. 18.
    Hegen A, Koidl S, Weindel K, Marme D, Augustin HG, Fiedler U (2004) Expression of angiopoietin-2 in endothelial cells is controlled by positive and negative regulatory promoter elements. Arterioscler Thromb Vasc Biol 24:1803–1809PubMedCrossRefGoogle Scholar
  19. 19.
    Pauling MH, Vu TH (2004) Mechanisms and regulation of lung vascular development. Curr Top Dev Biol 64:73–99PubMedCrossRefGoogle Scholar
  20. 20.
    Konac E, Onen HI, Metindir J, Alp E, Biri AA, Ekmekci A (2007) Lack of association between −460 C/T and 936 C/T of the vascular endothelial growth factor and angiopoietin-2 exon 4 G/A polymorphisms and ovarian, cervical, and endometrial cancers. DNA Cell Biol 26:453–463PubMedCrossRefGoogle Scholar
  21. 21.
    Dunai G, Vasarhelyi B, Szabo M, Hajdu J, Meszaros G, Tulassay T, Treszl A (2008) Published genetic variants in retinopathy of prematurity: random forest analysis suggests a negligible contribution to risk and severity. Curr Eye Res 33:501–505PubMedCrossRefGoogle Scholar
  22. 22.
    Menezes SL, Bozza PT, Neto HC, Laranjeira AP, Negri EM, Capelozzi VL, Zin WA, Rocco PR (2005) Pulmonary and extrapulmonary acute lung injury: inflammatory and ultrastructural analyses. J Appl Physiol 98:1777–1783PubMedCrossRefGoogle Scholar
  23. 23.
    Riva DR, Oliveira MB, Rzezinski AF, Rangel G, Capelozzi VL, Zin WA, Morales MM, Pelosi P, Rocco PR (2008) Recruitment maneuver in pulmonary and extrapulmonary experimental acute lung injury. Crit Care Med 36:1900–1908PubMedCrossRefGoogle Scholar
  24. 24.
    Daly C, Pasnikowski E, Burova E, Wong V, Aldrich TH, Griffiths J, Ioffe E, Daly TJ, Fandl JP, Papadopoulos N, McDonald DM, Thurston G, Yancopoulos GD, Rudge JS (2006) Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells. Proc Natl Acad Sci USA 103:15491–15496PubMedCrossRefGoogle Scholar
  25. 25.
    Mandriota SJ, Pepper MS (1998) Regulation of angiopoietin-2 mRNA levels in bovine microvascular endothelial cells by cytokines and hypoxia. Circ Res 83:852–859PubMedGoogle Scholar
  26. 26.
    Zhai R, Zhou W, Gong MN, Thompson BT, Su L, Yu C, Kraft P, Christiani DC (2007) Inhibitor kappaB-alpha haplotype GTC is associated with susceptibility to acute respiratory distress syndrome in Caucasians. Crit Care Med 35:893–898PubMedCrossRefGoogle Scholar
  27. 27.
    Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, LeGall JR, Morris A, Spragg R (1994) Report of the American–European consensus conference on ARDS: definitions, mechanisms, relevant outcomes and clinical trial coordination. The consensus committee. Intensive Care Med 20:225–232PubMedCrossRefGoogle Scholar
  28. 28.
    Kraft P, Cox DG, Paynter RA, Hunter D, De Vivo I (2005) Accounting for haplotype uncertainty in matched association studies: a comparison of simple and flexible techniques. Genet Epidemiol 28:261–272PubMedCrossRefGoogle Scholar
  29. 29.
    Benjamini Y, Yekutieli D (2005) Quantitative trait loci analysis using the false discovery rate. Genetics 171:783–790PubMedCrossRefGoogle Scholar
  30. 30.
    Chapman JM, Cooper JD, Todd JA, Clayton DG (2003) Detecting disease associations due to linkage disequilibrium using haplotype tags: a class of tests and the determinants of statistical power. Hum Hered 56:18–31PubMedCrossRefGoogle Scholar
  31. 31.
    Ganter MT, Cohen MJ, Brohi K, Chesebro BB, Staudenmayer KL, Rahn P, Christiaans SC, Bir ND, Pittet JF (2008) Angiopoietin-2, marker and mediator of endothelial activation with prognostic significance early after trauma? Ann Surg 247:320–326PubMedCrossRefGoogle Scholar
  32. 32.
    van der Heijden M, van Nieuw Amerongen GP, Koolwijk P, van Hinsbergh VW, Groeneveld AJ (2008) Angiopoietin-2, permeability oedema, occurrence and severity of ALI/ARDS in septic and non-septic critically ill patients. Thorax 63:903–909PubMedCrossRefGoogle Scholar
  33. 33.
    Gong MN, Zhou W, Williams PL, Thompson BT, Pothier L, Boyce P, Christiani DC (2005) -308GA and TNFB polymorphisms in acute respiratory distress syndrome. Eur Respir J 26:382–389PubMedCrossRefGoogle Scholar
  34. 34.
    Pelosi P, D’Onofrio D, Chiumello D, Paolo S, Chiara G, Capelozzi VL, Barbas CS, Chiaranda M, Gattinoni L (2003) Pulmonary and extrapulmonary acute respiratory distress syndrome are different. Eur Respir J Suppl 42:48s–56sPubMedCrossRefGoogle Scholar
  35. 35.
    Negri EM, Hoelz C, Barbas CS, Montes GS, Saldiva PH, Capelozzi VL (2002) Acute remodeling of parenchyma in pulmonary and extrapulmonary ARDS. An autopsy study of collagen-elastic system fibers. Pathol Res Pract 198:355–361PubMedCrossRefGoogle Scholar
  36. 36.
    Santos FB, Nagato LK, Boechem NM, Negri EM, Guimaraes A, Capelozzi VL, Faffe DS, Zin WA, Rocco PR (2006) Time course of lung parenchyma remodeling in pulmonary and extrapulmonary acute lung injury. J Appl Physiol 100:98–106PubMedCrossRefGoogle Scholar
  37. 37.
    dos Santos CC, Okutani D, Hu P, Han B, Crimi E, He X, Keshavjee S, Greenwood C, Slutsky AS, Zhang H, Liu M (2008) Differential gene profiling in acute lung injury identifies injury-specific gene expression. Crit Care Med 36:855–865PubMedCrossRefGoogle Scholar
  38. 38.
    Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG (2001) Replication validity of genetic association studies. Nat Genet 29:306–309PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Li Su
    • 1
  • Rihong Zhai
    • 1
  • Chau-Chyun Sheu
    • 1
  • Diana C. Gallagher
    • 2
  • Michelle N. Gong
    • 3
  • Paula Tejera
    • 1
  • B. Taylor Thompson
    • 4
  • David C. Christiani
    • 1
    • 4
    Email author
  1. 1.Department of Environmental HealthHarvard School of Public HealthBostonUSA
  2. 2.Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA
  3. 3.Division of Pulmonary and Critical Care MedicineMount Sinai School of MedicineNew YorkUSA
  4. 4.Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General HospitalHarvard Medical SchoolBostonUSA

Personalised recommendations