Genetic variation in the FAS gene and associations with acute lung injury.
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.
Glavan
Bradford J
BJ
Section of Pulmonary/Critical Care Medicine, Harborview Medical Center, Seattle, Washington, USA. bglavan@u.washington.edu
Holden
Tarah D
TD
Goss
Christopher H
CH
Black
R Anthony
RA
Neff
Margaret J
MJ
Nathens
Avery B
AB
Martin
Thomas R
TR
Wurfel
Mark M
MM
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*
C491901:FAS protein, human; D019014:fas Receptor
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