ANGPT2 genetic variant is associated with trauma-associated acute lung injury and altered plasma angiopoietin-2 isoform ratio.
BACKGROUND
Acute lung injury (ALI) acts as a complex genetic trait, yet its genetic risk factors remain incompletely understood. Large-scale genotyping has not previously been reported for ALI.


OBJECTIVE
To identify ALI risk variants after major trauma using a large-scale candidate gene approach.


METHODS
We performed a two-stage genetic association study. We derived findings in an African American cohort (n = 222) using a cardiopulmonary disease-centric 50K single nucleotide polymorphism (SNP) array. Genotype and haplotype distributions were compared between subjects with ALI and without ALI, with adjustment for clinical factors. Top performing SNPs (P < 10(-4)) were tested in a multicenter European American trauma-associated ALI case-control population (n = 600 ALI; n = 2,266 population-based control subjects) for replication. The ALI-associated genomic region was sequenced, analyzed for in silico prediction of function, and plasma was assayed by ELISA and immunoblot.


RESULTS
Five SNPs demonstrated a significant association with ALI after adjustment for covariates in Stage I. Two SNPs in ANGPT2 (rs1868554 and rs2442598) replicated their significant association with ALI in Stage II. rs1868554 was robust to multiple comparison correction: odds ratio 1.22 (1.06-1.40), P = 0.0047. Resequencing identified predicted novel splice sites in linkage disequilibrium with rs1868554, and immunoblots showed higher proportion of variant angiopoietin-2 (ANG2) isoform associated with rs1868554T (0.81 vs. 0.48; P = 0.038).


CONCLUSIONS
An ANGPT2 region is associated with both ALI and variation in plasma angiopoietin-2 isoforms. Characterization of the variant isoform and its genetic regulation may yield important insights about ALI pathogenesis and susceptibility.
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. nuala.meyer@uphs.upenn.edu
Nuala J
NJ
Meyer
Mingyao
M
Li
Rui
R
Feng
Jonathan
J
Bradfield
Robert
R
Gallop
Scarlett
S
Bellamy
Barry D
BD
Fuchs
Paul N
PN
Lanken
Steven M
SM
Albelda
Melanie
M
Rushefski
Richard
R
Aplenc
Helen
H
Abramova
Elena N
EN
Atochina-Vasserman
Michael F
MF
Beers
Carolyn S
CS
Calfee
Mitchell J
MJ
Cohen
Jean-Francois
JF
Pittet
David C
DC
Christiani
Grant E
GE
O'Keefe
Lorraine B
LB
Ware
Addison K
AK
May
Mark M
MM
Wurfel
Hakon
H
Hakonarson
Jason D
JD
Christie
D055371:Acute Lung Injury / Q000097:blood* / Q000235:genetics*; D000328:Adult; D042702:Angiopoietin-2 / Q000097:blood* / Q000235:genetics*; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020033:Protein Isoforms; D012307:Risk Factors
D042702:Angiopoietin-2; D020033:Protein Isoforms
Nat Genet. 2001 Mar;27(3):234-6
11242096
J Trauma. 1988 Jan;28(1):87-90
3339667
Bioinformatics. 2008 Dec 15;24(24):2938-9
18974171
Genet Epidemiol. 2003 Sep;25(2):149-57
12916023
Clin Chest Med. 2006 Dec;27(4):705-24; abstract x
17085257
Am J Respir Crit Care Med. 2011 Feb 1;183(3):356-63
20813889
Intensive Care Med. 2009 Feb;35(2):248-57
18670758
Cancer Res. 2006 Apr 1;66(7):3649-57
16585190
FASEB J. 2007 Jul;21(9):2237-46
17384144
Science. 1997 Jul 4;277(5322):55-60
9204896
Curr Biol. 2010 Feb 23;20(4):R166-73
20178763
PLoS One. 2008;3(10):e3583
18974833
J Cell Mol Med. 2009 Aug;13(8B):1784-1791
19017358
Am J Respir Crit Care Med. 2005 Feb 15;171(4):361-70
15579727
Science. 2002 Jun 21;296(5576):2225-9
12029063
J Immunol. 2009 Feb 15;182(4):2277-87
19201882
Am J Physiol Lung Cell Mol Physiol. 2009 May;296(5):L713-25
19218355
Crit Care Med. 2007 Aug;35(8):1821-8
17667242
Am J Hum Genet. 2009 Nov;85(5):628-42
19913121
PLoS Med. 2006 Mar;3(3):e46
16417407
Nature. 2007 Aug 2;448(7153):591-4
17632545
Eur J Intern Med. 2007 Jul;18(4):267-71
17574099
Crit Care. 2008;12(5):R130
18950526
Thorax. 2005 Mar;60(3):244-8
15741444
Nucleic Acids Res. 2003 Jul 1;31(13):3568-71
12824367
Annu Rev Genomics Hum Genet. 2009;10:387-406
19715440
Crit Care. 2009;13(6):R174
19887013
J Biol Chem. 2000 Jun 16;275(24):18550-6
10766762
Am J Respir Cell Mol Biol. 2006 Apr;34(4):487-95
16399953
Nat Genet. 2010 Mar;42(3):234-9
20154673
Crit Care Med. 2008 Aug;36(8):2309-15
18664786
Ann Intern Med. 2004 Sep 21;141(6):440-5
15381517
Epidemiology. 2008 Sep;19(5):649-51; discussion 657-8
18703928
Chest. 2010 Nov;138(5):1054-61
20576730
N Engl J Med. 2005 Oct 20;353(16):1685-93
16236739
Nat Med. 2006 Nov;12(11):1286-93
17086189
Am J Respir Crit Care Med. 1994 Mar;149(3 Pt 1):818-24
7509706
Crit Care Med. 2007 Jan;35(1):199-206
17110873
Bioinformatics. 2005 Jan 15;21(2):263-5
15297300
Intensive Care Med. 2009 Jun;35(6):1024-30
19271210
Nature. 2007 Jun 7;447(7145):661-78
17554300
Nature. 2007 Oct 18;449(7164):851-61
17943122
Circ Cardiovasc Genet. 2010 Jun;3(3):267-75
20400780
Science. 2002 Aug 9;297(5583):1007-13
12114529
Crit Care Med. 2008 Oct;36(10):2794-800
18828194
Genes Dev. 2004 Jun 1;18(11):1241-50
15145827
Nucleic Acids Res. 2009 May;37(9):e67
19339519
Am J Hum Genet. 2007 Sep;81(3):559-75
17701901
Nat Rev Genet. 2008 May;9(5):356-69
18398418
Shock. 2008 Jun;29(6):656-61
18091573
BMC Proc. 2009 Dec 15;3 Suppl 7:S5
20018042
Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5797-802
18391195
Eur Respir J. 2009 Mar;33(3):543-50
19010984
Cell Cycle. 2007 May 2;6(9):1049-52
17438375
Hum Mol Genet. 2010 Aug 1;19(15):3080-8
20466734
Proc Am Thorac Soc. 2005;2(3):195-201
16222037
N Engl J Med. 2009 Dec 24;361(26):2518-28
20032323
Chest. 2009 Apr;135(4):944-949
19118274
Chest. 2007 Oct;132(4):1116-23
17505028
Shock. 2007 Dec;28(6):650-654
18092380
Nature. 2007 Jun 7;447(7145):655-60
17554299
J Trauma. 2010 May;68(5):1121-7
20038857
Am J Respir Crit Care Med. 2008 Oct 1;178(7):710-20
18635889
Circ Cardiovasc Genet. 2010 Apr;3(2):147-54
20124441
J Trauma. 2009 Jan;66(1):115-22; discussion 122-3
19131814