Genetic Variation in NFKBIE Is Associated With Increased Risk of Pneumococcal Meningitis in Children

EBioMedicine. 2015 Dec 2;3:93-99. doi: 10.1016/j.ebiom.2015.11.048. eCollection 2016 Jan.


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.

Keywords: CI, confidence intervals; CRS, Danish Civil Registration System; CSF, cerebrospinal fluid; DNPR, Danish National Patient Registry; DNSB, Danish Neonatal Screening Biobank; HWE, Hardy–Weinberg equilibrium; IMD, invasive meningococcal disease; IPD, Invasive pneumococcal disease; IQR, interquartile range; Invasive Meningococcal Disease; Invasive Pneumococcal Disease; LD, linkage disequilibrium; NF, nuclear factor-κB; Nuclear Factor-κB; OR, odds ratio; Pneumoccoccal Serotypes; RSV, respiratory syncytial virus; SNPs, single nucleotide polymorphisms; SSI, Statens Serum Institut; WGA, whole-genome-amplification; aOR, adjusted odds ratio.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Case-Control Studies
  • Child, Preschool
  • Denmark / epidemiology
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Genotype
  • Humans
  • I-kappa B Proteins / genetics*
  • Infant
  • Infant, Newborn
  • Male
  • Meningitis, Pneumococcal / genetics*
  • Meningitis, Pneumococcal / microbiology
  • Meningitis, Pneumococcal / mortality
  • Odds Ratio
  • Polymorphism, Single Nucleotide
  • Prognosis
  • Proto-Oncogene Proteins / genetics*
  • Registries
  • Risk
  • Streptococcus pneumoniae


  • I-kappa B Proteins
  • NFKBIE protein, human
  • Proto-Oncogene Proteins