title: Genetic polymorphisms associated with the inflammatory response in bacterial meningitis.
abstract: BACKGROUND
  Bacterial meningitis (BM) is an infectious disease that results in high mortality and morbidity. Despite efficacious antibiotic therapy, neurological sequelae are often observed in patients after disease. Currently, the main challenge in BM treatment is to develop adjuvant therapies that reduce the occurrence of sequelae. In recent papers published by our group, we described the associations between the single nucleotide polymorphisms (SNPs) AADAT +401C > T, APEX1 Asn148Glu, OGG1 Ser326Cys and PARP1 Val762Ala and BM. In this study, we analyzed the associations between the SNPs TNF -308G > A, TNF -857C > T, IL-8 -251A > T and BM and investigated gene-gene interactions, including the SNPs that we published previously.
  
  
  METHODS
  The study was conducted with 54 BM patients and 110 healthy volunteers (as the control group). The genotypes were investigated via primer-introduced restriction analysis-polymerase chain reaction (PIRA-PCR) or polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) analysis. Allelic and genotypic frequencies were also associated with cytokine and chemokine levels, as measured with the x-MAP method, and cell counts. We analyzed gene-gene interactions among SNPs using the generalized multifactor dimensionality reduction (GMDR) method.
  
  
  RESULTS
  We did not find significant association between the SNPs TNF -857C > T and IL-8 -251A > T and the disease. However, a higher frequency of the variant allele TNF -308A was observed in the control group, associated with changes in cytokine levels compared to individuals with wild type genotypes, suggesting a possible protective role. In addition, combined inter-gene interaction analysis indicated a significant association between certain genotypes and BM, mainly involving the alleles APEX1 148Glu, IL8 -251 T and AADAT +401 T. These genotypic combinations were shown to affect cyto/chemokine levels and cell counts in CSF samples from BM patients.
  
  
  CONCLUSIONS
  In conclusion, this study revealed a significant association between genetic variability and altered inflammatory responses, involving important pathways that are activated during BM. This knowledge may be useful for a better understanding of BM pathogenesis and the development of new therapeutic approaches.
authors: Departamento de Biologia Celular e Genética, Universidade Federal do Rio Grande do Norte, UFRN, Natal, Brazil. fontesfl@hotmail.com.
authors: Fabrícia Lima
authors: FL
authors: Fontes
authors: Departamento de Biologia Celular e Genética, Universidade Federal do Rio Grande do Norte, UFRN, Natal, Brazil. luizaferreiraaraujo@gmail.com.
authors: Luíza Ferreira
authors: LF
authors: de Araújo
authors: Departamento de Biologia Celular e Genética, Universidade Federal do Rio Grande do Norte, UFRN, Natal, Brazil. leonam_manoel@yahoo.com.
authors: Leonam Gomes
authors: LG
authors: Coutinho
authors: Institute for Infectious Diseases, University of Bern, Friedbuehlstrasse 51, CH-3010, Bern, Switzerland. stephen.leib@ifik.unibe.ch.
authors: Stephen L
authors: SL
authors: Leib
authors: Departamento de Biologia Celular e Genética, Universidade Federal do Rio Grande do Norte, UFRN, Natal, Brazil. lfagnez@ufrnet.br.|Departamento de Biologia Celular e Genética, Centro de Biociências - UFRN, Campus Universitário, Lagoa Nova, Natal, RN, 59078-970, Brazil. lfagnez@ufrnet.br.
authors: Lucymara Fassarella
authors: LF
authors: Agnez-Lima
mesh_terms: D001938:Brazil; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D016209:Interleukin-8 / Q000235:genetics*; D008297:Male; D016920:Meningitis, Bacterial / Q000235:genetics*; D016017:Odds Ratio; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018709:Statistics, Nonparametric; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha