title: Genetic Variation in NFKBIE Is Associated With Increased Risk of Pneumococcal Meningitis in Children.
abstract: 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.
authors: Department of Infectious Diseases, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark; Clinical Research Centre, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark; Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: lene.lundbo@gmail.com.
authors: Lene F
authors: LF
authors: Lundbo
authors: Division of Diagnostics and Infection Control, Statens Serum Institut, Copenhagen, Denmark; Department for Pulmonary and Infectious Diseases, North Zealand Hospital Hillerød, Hillerød, Denmark.
authors: Zitta Barrella
authors: ZB
authors: Harboe
authors: Department of Infectious Diseases, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark.
authors: Louise N
authors: LN
authors: Clausen
authors: Danish Centre for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
authors: Mads V
authors: MV
authors: Hollegaard
authors: Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
authors: Henrik T
authors: HT
authors: Sørensen
authors: Danish Centre for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
authors: David M
authors: DM
authors: Hougaard
authors: Division of Diagnostics and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
authors: Helle B
authors: HB
authors: Konradsen
authors: Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
authors: Mette
authors: M
authors: Nørgaard
authors: Department of Infectious Diseases, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark; Clinical Research Centre, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark; Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: tlb@dadlnet.dk.
authors: Thomas
authors: T
authors: Benfield
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D002675:Child, Preschool; D003718:Denmark / Q000453:epidemiology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008586:Meningitis, Pneumococcal / Q000235:genetics* / Q000382:microbiology / Q000401:mortality; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012042:Registries; D012306:Risk; D013296:Streptococcus pneumoniae
chemical_list: D020672:I-kappa B Proteins; C105627:NFKBIE protein, human; D011518:Proto-Oncogene Proteins
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