Genetic variants in the angiopoietin-2 gene are associated with increased risk of ARDS
- 184 Downloads
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; P = 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.
KeywordsAngiopoietin-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.
- 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
- 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
- 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
- 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