Abstract
BackgroundFormyl peptide receptor 2-lipoxin receptor (FPR2/ALX) modulates the anti-inflammatory response and therefore may be a target for treating sepsis. The purpose of this study was to investigate the association between genetic variants of the FPR2/ALX gene and sepsis after severe trauma as well as to further analyze the functions of sepsis-related genetic polymorphisms.MethodsThree tag single-nucleotide polymorphisms (tag SNPs) that captured all common alleles across the FPR2/ALX genomic region were genotyped using pyrosequencing in an initial sample consisting of 275 patients with severe trauma. The rs11666254 polymorphism, which had statistical significance, was genotyped in an additional 371 patients, and logistic regression analysis was performed to determine associations between the FPR2/ALX gene polymorphism and sepsis susceptibility after severe trauma. The messenger RNA (mRNA) and protein levels of FPR2/ALX in the lipopolysaccharide-stimulated white blood cells of trauma patients were determined by performing quantitative polymerase chain reactions and Western blot analysis. Tumor necrosis factor (TNF)-α production was measured by enzyme-linked immunosorbent assay. The effects of the promoter polymorphism rs11666254 on the transcription activity of FPR2/ALX were analyzed using a luciferase reporter assay.ResultsAmong the three tag SNPs, only the rs11666254 polymorphism was found to be significantly associated with sepsis in trauma patients, and this association persisted after a pooled analysis of all 646 trauma patients, which showed that patients who carried the A allele of rs11666254 had a significantly higher risk of developing sepsis than individuals who carried the G allele. This SNP was also significantly associated with lower FPR2/ALX mRNA and protein expression as well as higher TNF-α production from the peripheral blood leukocyte response to bacterial lipoprotein stimulation. In addition, the rs11666254 polymorphism could significantly decrease the promoter activity of the FPR2/ALX gene.ConclusionsThe rs11666254 polymorphism in the FPR2/ALX gene is a functional SNP that increases sepsis susceptibility in patients after traumatic injury.
Highlights
Formyl peptide receptor 2-lipoxin receptor (FPR2/ALX) modulates the anti-inflammatory response and may be a target for treating sepsis
The messenger RNA and protein levels of FPR2/ALX are reduced by approximately ten- and threefold, respectively, in neutrophils of individuals carrying the a single-nucleotide mutation (A/G) mutation compared with cells from individuals expressing the wild-type allele [29]. These findings suggest that genetic variants of FPR2/ALX may play an important role in regulating gene expression and influence the anti-inflammatory processes in patients with sepsis
We identify, for the first time to our knowledge, an single-nucleotide polymorphism (SNP) located in the promoter of FPR2/ALX that is associated with increased sepsis hypersensitivity in major trauma patients
Summary
Formyl peptide receptor 2-lipoxin receptor (FPR2/ALX) modulates the anti-inflammatory response and may be a target for treating sepsis. Increasing evidence suggests that SNPs are critical for determining interindividual differences in both inflammatory responses and clinical outcomes in sepsis patients [5, 6]. Identifying the polymorphisms and associated interindividual differences may assist with the risk stratification of trauma patients at the early stages of trauma and might contribute to developing new genetically based diagnostic and therapeutic interventions that alter host susceptibility to sepsis-related outcomes. These studies are not compared, owing to the relatively small sample sizes and different study populations [13]. Some SNPs clearly appear to be associated with the disease, no definitive conclusions currently can be drawn regarding the influence of specific sequence variations on outcomes in trauma patients [13]
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