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- Title
Genetic variation in the FAS gene and associations with acute lung injury.
- Authors
Glavan BJ; Holden TD; Goss CH; Black RA; Neff MJ; Nathens AB; Martin TR; Wurfel MM; ARDSnet Investigators; Glavan, Bradford J; Holden, Tarah D; Goss, Christopher H; Black, R Anthony; Neff, Margaret J; Nathens, Avery B; Martin, Thomas R; Wurfel, Mark M
- Abstract
<bold>Rationale: </bold>Fas (CD95) modulates apoptosis and inflammation and is believed to play an important role in lung injury.<bold>Objectives: </bold>To determine if common genetic variation in FAS is associated with acute lung injury (ALI) susceptibility, risk of death, and FAS gene expression.<bold>Methods: </bold>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.<bold>Measurements and Main Results: </bold>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.<bold>Conclusions: </bold>Common genetic variants in FAS are associated with ALI susceptibility. This is the first genetic evidence supporting a role for FAS in ALI.
- Subjects
ANTIGENS; DISEASE susceptibility; GENES; GENETIC polymorphisms; GENETICS; GENETIC techniques; LUNG injuries; RESEARCH funding; CASE-control method; ACUTE diseases; GENOTYPES
- Publication
American Journal of Respiratory & Critical Care Medicine, 2011, Vol 183, Issue 3, p356
- ISSN
1073-449X
- Publication type
journal article
- DOI
10.1164/rccm.201003-0351OC