Study of the association between Single Nucleotide Polymorphisms (SNPs) in genes of inflammatory mediators and the susceptibility the phenotype of pediatric sepsis.
Sepsis can be defined as sistemic inflammatory response syndrome that occurs during the course of an infection. Recent advances in genomic studies made possible the description of genetic polymorphisms that could be correlated with the heterogeneity of the clinical presentations and the susceptibility to many infectious diseases, as well as sepsis. Amongst these are the Single Nucleotide Polymorphisms (SNPs) located in the genes coding for inflammatory mediators that could be involved in the control of gene expression. The level of expression of these mediators could modulate the immunologic response of the individual against infection and, consequently, influence the clinical outcome. In this study we evaluated the SNPs in positions -308 (Gamp;#61614;A) and - 863 (C amp;#61614;A) of the tumor necrosis factor-alpha (TNFamp;#61537;) gene, +252 (Gamp;#61614;A) of the lymphotoxin-alpha (LTamp;#61537;) gene, -173 (Gamp;#61614;C) in the Macrophage Migration Inhibitory Factor gene (MIF) gene and -159 (Camp;#61614;T) of the CD14 gene with respect to the clinical outcomes and susceptibility. For this, the allelic and genotipic frequencies of the SNPs were compared in a case-control study design. We enrolled 228 patients with the clinical diagnosis of sepsis clinical from the Intensive Care Unit of the Fernandes Figueira Institute-FIOCRUZ (UPG-IFF) and 79 patients without sepsis, of both genders, with age range between 0 and 17 years. The molecular determination of all the genotypes was carried out through PCR-RFLP and ARMS-PCR methods. All loci studied were in Hardy-Weinberg Equilibrium. The allelic and genotypic frequencies were compared using logistic regression techniques. No association of any genotypes and alleles studied with the sepsis was found. However, individuals heterozigotes (CA) for the TNF-863 SNP presented a three-fold increased risk of development of the most severe forms of Multiple Systems Organs Disfunction (MSOD). In addition the -863A carriers presented two-fold increased probability of developing Acute Respiratory Distress Syndrome (ARDS), and a three-fold increase to develop the most severe forms of MSOD. In this way, the SNP TNF-863 seems to behave as an genetic marker of prognostic value concerning the evolution for the severity of pediatric sepsis.
Advisor:Maria Ignez Capella Gaspar Elsas; Milton Ozório Moraes
School:Faculdades Oswaldo Cruz
Source Type:Master's Thesis
Polymorphism Single Nucleotide
Tumor Necrosis Factor-alpha
Date of Publication:02/01/2007