Abstract
Bacterial meningitis (BM) is a serious infection of the central nervous system, frequently occurring in childhood and often resulting in hearing loss, learning disabilities, and encephalopathy. Previous studies showed that genetic variation in innate immune response genes affects susceptibility, severity, and outcome of BM. The aim of this study is to describe whether single nucleotide polymorphisms (SNPs) in pathogen recognition gene products are associated with susceptibility to develop BM in single genes analysis as well as SNP combinations. Genotype frequencies of seven SNPs, in five immune response genes encoding for Toll-like receptors (TLRs), nucleotide oligomerization domain (NOD) proteins and caspase-1 (CASP1), in 391 children with meningococcal meningitis (MM) and 82 children with pneumococcal meningitis were compared with a large cohort of 1141 ethnically matched healthy controls. Carriage of TLR4 +896 GG mutant predisposed to susceptibility to develop MM (p = 1.2*10−5, OR = 9.4, 95% CI = 3.0–29.2). The NOD2 SNP8 mutant was significantly more frequent in MM patients compared to controls (p = 0.0004, OR = 12.2, 95% CI = 2.6–57.8). Combined carriage of TLR2 +2477 and TLR4 +896 mutants was strongly associated with MM (p = 4.2*10−5, OR = 8.6, 95% CI = 2.7–27.3). A carrier trait of TLR4 +896 and NOD2 SNP8 mutants was also strongly associated with susceptibility to develop MM (p = 4.2*10−5, OR = 10.6, 95% CI = 2.9–38.6). This study associates SNPs in TLR4 and NOD2 with susceptibility to develop MM.
Highlights
Susceptibility to infections is determined by genetic variation in human populations as can be concluded from genetic epidemiology studies
In the cases TLR2, TLR9, NOD1, and CASP1 single nucleotide polymorphisms (SNPs) were in Hardy-Weinberg Equilibrium (HWE), TLR4 and NOD2 SNPs were not in HWE
Comparing genotype frequencies between Bacterial meningitis (BM) survivors and healthy controls we showed that TLR4 +896 and NOD2 SNP8 were significantly associated with susceptibility to develop meningococcal meningitis (MM)
Summary
Susceptibility to infections is determined by genetic variation in human populations as can be concluded from genetic epidemiology studies. Bacterial meningitis (BM) is a severe infectious disease of the central nervous system (CNS). It occurs relatively frequent in childhood and often affects hearing and learning abilities [3,4]. Genetic variation in genes encoding for pathogen recognizing receptors (PRRs), such as Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD) like receptors (NLRs), can lead to enhanced or decreased inflammatory responses in several cell types such as macrophages and epithelial cells [6]. The resident macrophages inside the CNS, and neuro-epithelial cells express TLRs and NLRs. genetic variation in these receptors might influence susceptibility, severity and outcome of BM
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