title: IkappaB genetic polymorphisms and invasive pneumococcal disease.
abstract: BACKGROUND
  Increasing evidence supports a key role for the transcription factor nuclear factor (NF)-kappaB in the host response to pneumococcal infection. Control of NF-kappaB activity is achieved through interactions with the IkappaB family of inhibitors, encoded by the genes NFKBIA, NFKBIB, and NFKBIE. Rare NFKBIA mutations cause immunodeficiency with severe bacterial infection, raising the possibility that common IkappaB gene polymorphisms confer susceptibility to common bacterial disease.
  
  
  OBJECTIVE
  To determine whether polymorphisms in NFKBIA, NFKBIB, and NFKBIE associate with susceptibility to invasive pneumococcal disease (IPD) and thoracic empyema.
  
  
  METHODS
  We studied the frequencies of 62 single-nucleotide polymorphisms (SNPs) across NFKBIA, NFKBIB, and NFKBIE in individuals with IPD and control subjects (n=1,060). Significantly associated SNPs were then studied in a group of individuals with thoracic empyema and a second control group (n=632).
  
  
  RESULTS
  Two SNPs in the NFKBIA promoter region were associated with protection from IPD in both the initial study group and the pneumococcal empyema subgroup. Significant protection from IPD was observed for carriage of mutant alleles at these two loci on combining the groups (SNP rs3138053: Mantel-Haenszel 2x2 chi2=13.030, p=0.0003; odds ratio [OR], 0.60; 95% confidence interval [CI], 0.45-0.79; rs2233406: Mantel-Haenszel 2x2 chi2=18.927, p=0.00001; OR, 0.55; 95% CI, 0.42-0.72). An NFKBIE SNP associated with susceptibility to IPD but not pneumococcal empyema. None of the NFKBIB SNPs associated with IPD susceptibility.
  
  
  CONCLUSIONS
  NFKBIA polymorphisms associate with susceptibility to IPD. Genetic variation in an inhibitor of NF-kappaB therefore not only causes a very rare immunodeficiency state but may also influence the development of common infectious disease.
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, and Oxford Centre for Respiratory Medicine, Churchill Hospital Site, Oxford Radcliffe Hospital, Roosevelt Drive, Oxford, OX3 7BN, UK. schapman@well.ox.ac.uk
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chapman
authors.forename: Chiea C
authors.initials: CC
authors.lastname: Khor
authors.forename: Fredrik O
authors.initials: FO
authors.lastname: Vannberg
authors.forename: Angela
authors.initials: A
authors.lastname: Frodsham
authors.forename: Andrew
authors.initials: A
authors.lastname: Walley
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Maskell
authors.forename: Christopher W H
authors.initials: CW
authors.lastname: Davies
authors.forename: Shelley
authors.initials: S
authors.lastname: Segal
authors.forename: Catrin E
authors.initials: CE
authors.lastname: Moore
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Gillespie
authors.forename: Paul
authors.initials: P
authors.lastname: Denny
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Day
authors.forename: Derrick W
authors.initials: DW
authors.lastname: Crook
authors.forename: Robert J O
authors.initials: RJ
authors.lastname: Davies
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D016724:Empyema, Pleural / Q000235:genetics* / Q000382:microbiology; D020022:Genetic Predisposition to Disease; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics*; D000072000:NF-KappaB Inhibitor alpha; D011008:Pneumococcal Infections / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: C083487:I kappa B beta protein; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; C105627:NFKBIE protein, human; D011518:Proto-Oncogene Proteins; D000072000:NF-KappaB Inhibitor alpha