Bradford J. Glavan1, Tarah D. Holden1, Christopher H. Goss2, R. Anthony Black3, Margaret J. Neff1, Avery B. Nathens4, Thomas R. Martin5, Mark M. Wurfel1 ARDSnet Investigators. American Journal of Respiratory and Critical Care Medicine Vol 183. pp. 356-363, (2011). Published ahead of print on September 2, 2010, doi:10.1164/rccm.201003-0351OC
Rationale: Fas (CD95) modulates apoptosis and inflammation and is believed to play an important role in lung injury.

Objectives: 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.

Measurements and Main Results: We identified associations between four tagSNPs in FAS (FAS–11341A>T [rs17447140], FAS9325G>A [rs2147420], FAS21541C>T [rs2234978], and FAS24484A>T [rs1051070]) and ALI case status. Haplotype-based analyses suggested that three of the tagSNPs (FAS9325G>A, FAS21541C>T, and FAS24484A>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.

Key Words: adult respiratory distress syndrome • FAS receptor • genetic predisposition • apoptosis

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