ABSTRACT
Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, identifying variants in CCDC33 associated with susceptibility. Pneumococcal genetic variation explains a large amount of invasive potential (70%), but has no effect on severity. Serotype alone is insufficient to explain invasiveness, suggesting other pneumococcal factors are involved in progression to invasive disease. We identify pneumococcal genes involved in invasiveness including pspC and zmpD, and perform a human-bacteria interaction analysis. These genes are potential candidates for the development of more broadly-acting pneumococcal vaccines.
Subject(s)
Genetic Predisposition to Disease , Meningitis, Pneumococcal/genetics , Streptococcus pneumoniae/genetics , Adult , Aged , Bacterial Proteins/genetics , Female , Genetic Variation , Genome, Bacterial/genetics , Genome, Human/genetics , Genome-Wide Association Study , Host-Pathogen Interactions/genetics , Humans , Male , Meningitis, Pneumococcal/microbiology , Middle Aged , Prospective Studies , Proteins/genetics , Streptococcus pneumoniae/isolation & purificationABSTRACT
BACKGROUND: Streptococcus pneumoniae and Neisseria meningitidis are frequent pathogens in life-threatening infections. Genetic variation in the immune system may predispose to these infections. Nuclear factor-κB is a key component of the TLR-pathway, controlled by inhibitors, encoded by the genes NFKBIA, NFKBIE and NFKBIZ. We aimed to replicate previous findings of genetic variation associated with invasive pneumococcal disease (IPD), and to assess whether similar associations could be found in invasive meningococcal disease (IMD). METHODS: Cases with IPD and IMD and controls were identified by linking Danish national registries. DNA was obtained from the Danish Neonatal Screening Biobank. The association between SNPs and susceptibility to IPD and IMD, mortality and pneumococcal serotypes was investigated. RESULTS: 372 children with pneumococcal meningitis, 907 with pneumococcal bacteremia and 1273 controls were included. We included 406 cases with meningococcal meningitis, 272 with meningococcal bacteremia, and 672 controls. The NFKBIE SNP was associated with increased risk of pneumococcal meningitis (aOR 1.68; 95% CI: 1.20-2.36), but not bacteremia (aOR 1.08; 95% CI: 0.86-1.35). The remaining SNPs were not associated with susceptibility to invasive disease. None of the SNPs were associated with risk of IMD or mortality. CONCLUSIONS: A NFKBIE polymorphism was associated with increased risk of pneumococcal meningitis.
Subject(s)
Genetic Predisposition to Disease , Genetic Variation , I-kappa B Proteins/genetics , Meningitis, Pneumococcal/genetics , Proto-Oncogene Proteins/genetics , Alleles , Case-Control Studies , Child, Preschool , Denmark/epidemiology , Female , Gene Frequency , Genotype , Humans , Infant , Infant, Newborn , Male , Meningitis, Pneumococcal/microbiology , Meningitis, Pneumococcal/mortality , Odds Ratio , Polymorphism, Single Nucleotide , Prognosis , Registries , Risk , Streptococcus pneumoniaeABSTRACT
Background. Neisseria meningitidis is the cause of meningococcal bacteremia and meningitis, and nasopharyngeal colonization with this pathogen is common. The incidence of invasive disease is highest in infants, whereas adolescents more often are carriers. Altered regulation or dysfunction of the innate immune system may predispose to invasive meningococcal disease (IMD). In this study, we investigated the effect of genetic variation in the mannose-binding lectin gene, MBL2, and its promoter on susceptibility to IMD and IMD-associated mortality among children. Methods. Children (<5 years) diagnosed during 1982-2007 with IMD and controls were identified through Danish national registries. DNA was obtained from the Danish Neonatal Screening Biobank. The associations between MBL2 diplotypes and IMD susceptibility and 30- and 90-day mortality were investigated using logistic regression analysis. Results. We included 1351 children: 406 with meningitis, 272 with bacteremia, and 673 age- and sex-matched controls. Of the children studied, 1292 (96%) were successfully genotyped and assigned MBL2 diplotypes. The median age in IMD cases was 19.1 months (interquartile range [IQR], 8.8-32.2 months). Children with defective MBL2 diplotypes were not at higher risk for meningococcal meningitis than children with intermediate and normal diplotypes (odds ratio [OR] = 0.69; 95% confidence interval [CI], .47-1.02). Similar results were found for children with bacteremia and defective diplotypes (OR = 0.84; 95% CI, .53-1.32) as well as for all cases (OR = 0.75; 95% CI, .56-1.01). There was no association between MBL2 diplotypes and mortality. Conclusions. Defective MBL2 diplotypes did not predict either an increased IMD susceptibility or mortality in a Danish population of children.
