Genetic Variation in theFASGene and Associations with Acute Lung Injury
- 1 February 2011
- journal article
- Published by American Thoracic Society in American Journal of Respiratory and Critical Care Medicine
- Vol. 183 (3), 356-363
- https://doi.org/10.1164/rccm.201003-0351oc
Abstract
Fas (CD95) modulates apoptosis and inflammation and is believed to play an important role in lung injury. To determine if common genetic variation in FAS is associated with acute lung injury (ALI) susceptibility, risk of death, and FAS gene expression. 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. 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. Common genetic variants in FAS are associated with ALI susceptibility. This is the first genetic evidence supporting a role for FAS in ALI.Keywords
This publication has 46 references indexed in Scilit:
- The FAS −670A>G polymorphism influences susceptibility to systemic sclerosis phenotypesArthritis & Rheumatism, 2009
- A Genome-wide In Vitro Bacterial-Infection Screen Reveals Human Variation in the Host Response Associated with Inflammatory DiseaseAmerican Journal of Human Genetics, 2009
- Recent advances in genetic predisposition to clinical acute lung injuryAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2009
- Common Gene Variants in the Tumor Necrosis Factor (TNF) and TNF Receptor Superfamilies and NF-kB Transcription Factors and Non-Hodgkin Lymphoma RiskPLOS ONE, 2009
- Toll-like Receptor 1 Polymorphisms Affect Innate Immune Responses and Outcomes in SepsisAmerican Journal of Respiratory and Critical Care Medicine, 2008
- Genotypes and haplotypes of the VEGF gene are associated with higher mortality and lower VEGF plasma levels in patients with ARDSThorax, 2007
- Pulmonary-Artery versus Central Venous Catheter to Guide Treatment of Acute Lung InjuryNew England Journal of Medicine, 2006
- Statistical significance for genomewide studiesProceedings of the National Academy of Sciences, 2003
- 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions ConferenceIntensive Care Medicine, 2003
- Allelic discrimination using fluorogenic probes and the 5′ nuclease assayGenetic Analysis: Biomolecular Engineering, 1999