title: Genetic variation in the FAS gene and associations with acute lung injury.
abstract: BACKGROUND
  Fas (CD95) modulates apoptosis and inflammation and is believed to play an important role in lung injury.
  
  
  OBJECTIVE
  To determine if common genetic variation in FAS is associated with acute lung injury (ALI) susceptibility, risk of death, and FAS gene expression.
  
  
  METHODS
  We genotyped 14 single nucleotide polymorphisms (tagSNPS) in FAS in samples from healthy white volunteers (control subjects, n = 294) and patients with ALI (cases, n = 324) from the ARDSnet Fluid and Catheter Treatment Trial (FACTT). FAS genotypes associated with ALI in the discovery study were confirmed in a nested case-control validation study of critically ill patients at risk for ALI (n = 657). We also tested for associations between selected tagSNPS and FAS mRNA levels in whole blood from healthy control subjects exposed to media alone or LPS ex vivo.
  
  
  RESULTS
  We identified associations between four tagSNPs in FAS (FAS(-11341A>T) [rs17447140], FAS(9325G>A) [rs2147420], FAS(21541C>T) [rs2234978], and FAS(24484A>T) [rs1051070]) and ALI case status. Haplotype-based analyses suggested that three of the tagSNPs (FAS(9325G>A), FAS(21541C>T), and FAS(24484A>T)) function as a unit. The association with this haplotype and ALI was validated in a nested case-control study of at-risk subjects (P = 0.05). This haplotype was also associated with increased FAS mRNA levels in response to LPS stimulation. There was no association between FAS polymorphisms and risk of death among ALI cases.
  
  
  CONCLUSIONS
  Common genetic variants in FAS are associated with ALI susceptibility. This is the first genetic evidence supporting a role for FAS in ALI.
authors.affiliation: Section of Pulmonary/Critical Care Medicine, Harborview Medical Center, Seattle, Washington, USA. bglavan@u.washington.edu
authors.forename: Bradford J
authors.initials: BJ
authors.lastname: Glavan
authors.forename: Tarah D
authors.initials: TD
authors.lastname: Holden
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Goss
authors.forename: R Anthony
authors.initials: RA
authors.lastname: Black
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Neff
authors.forename: Avery B
authors.initials: AB
authors.lastname: Nathens
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Martin
authors.forename: Mark M
authors.initials: MM
authors.lastname: Wurfel
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D019014:fas Receptor / Q000235:genetics*
chemical_list: C491901:FAS protein, human; D019014:fas Receptor
references.citation: PLoS One. 2009;4(4):e5360
references.pmid: 19390683
references.citation: Am J Respir Cell Mol Biol. 1997 Sep;17(3):272-8
references.pmid: 9308912
references.citation: Am J Respir Crit Care Med. 2002 Sep 1;166(5):646-50
references.pmid: 12204859
references.citation: Intensive Care Med. 2003 Apr;29(4):530-8
references.pmid: 12664219
references.citation: Science. 1995 Jun 2;268(5215):1347-9
references.pmid: 7539157
references.citation: Chest. 2010 Nov;138(5):1054-61
references.pmid: 20576730
references.citation: Endocrinology. 2001 Jun;142(6):2593-9
references.pmid: 11356709
references.citation: N Engl J Med. 1996 Nov 28;335(22):1643-9
references.pmid: 8929361
references.citation: Genet Anal. 1999 Feb;14(5-6):143-9
references.pmid: 10084106
references.citation: Arthritis Rheum. 2009 Dec;60(12):3815-20
references.pmid: 19950259
references.citation: Crit Care Med. 2007 Mar;35(3):893-8
references.pmid: 17235259
references.citation: Am J Respir Crit Care Med. 2011 Feb 1;183(3):356-63
references.pmid: 20813889
references.citation: N Engl J Med. 2006 Jun 15;354(24):2564-75
references.pmid: 16714767
references.citation: Crit Care Med. 2003 Jun;31(6):1607-11
references.pmid: 12794394
references.citation: Crit Care Med. 2001 Apr;29(4):709-18
references.pmid: 11373453
references.citation: Am J Respir Crit Care Med. 2005 Feb 15;171(4):361-70
references.pmid: 15579727
references.citation: Diabetes. 2001 Aug;50(8):1741-8
references.pmid: 11473033
references.citation: Eur Respir J. 2005 Sep;26(3):382-9
references.pmid: 16135717
references.citation: Science. 2002 Jun 21;296(5576):2225-9
references.pmid: 12029063
references.citation: N Engl J Med. 2006 May 25;354(21):2213-24
references.pmid: 16714768
references.citation: Am J Physiol Lung Cell Mol Physiol. 2009 May;296(5):L713-25
references.pmid: 19218355
references.citation: Am J Respir Crit Care Med. 2000 Jan;161(1):85-90
references.pmid: 10619802
references.citation: Am J Hum Genet. 2004 Jan;74(1):106-20
references.pmid: 14681826
references.citation: Am J Respir Crit Care Med. 1995 Feb;151(2 Pt 1):293-301
references.pmid: 7842182
references.citation: J Immunol. 2006 Dec 1;177(11):8086-94
references.pmid: 17114483
references.citation: Proc Am Thorac Soc. 2005;2(3):214-20
references.pmid: 16222040
references.citation: N Engl J Med. 2005 Oct 20;353(16):1685-93
references.pmid: 16236739
references.citation: Am J Hum Genet. 2009 Aug;85(2):214-27
references.pmid: 19664744
references.citation: Am J Respir Crit Care Med. 1994 Mar;149(3 Pt 1):818-24
references.pmid: 7509706
references.citation: Thorax. 2007 Aug;62(8):718-22
references.pmid: 17289863
references.citation: Genome Biol. 2001;2(8):RESEARCH0032
references.pmid: 11532216
references.citation: Exp Biol Med (Maywood). 2006 May;231(5):522-33
references.pmid: 16636300
references.citation: J Immunol. 2005 Sep 15;175(6):4069-75
references.pmid: 16148156
references.citation: Genes Immun. 2008 Dec;9(8):689-96
references.pmid: 18685642
references.citation: Crit Care Med. 2008 Oct;36(10):2794-800
references.pmid: 18828194
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9440-5
references.pmid: 12883005
references.citation: Am J Physiol Lung Cell Mol Physiol. 2001 Aug;281(2):L328-35
references.pmid: 11435207
references.citation: Mol Med. 2008 Jul-Aug;14(7-8):465-75
references.pmid: 18368145
references.citation: Shock. 2003 Dec;20(6):493-6
references.pmid: 14625471
references.citation: Nat Rev Genet. 2001 Feb;2(2):91-9
references.pmid: 11253062
references.citation: Am J Pathol. 2002 Nov;161(5):1783-96
references.pmid: 12414525
references.citation: J Leukoc Biol. 2007 Sep;82(3):721-8
references.pmid: 17576821
references.citation: Chest. 1999 Nov;116(5):1347-53
references.pmid: 10559098
references.citation: Am J Respir Crit Care Med. 2008 Oct 1;178(7):710-20
references.pmid: 18635889