NFKBIZ polymorphisms and susceptibility to pneumococcal disease in European and African populations
Open Access
- 1 October 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in Genes & Immunity
- Vol. 11 (4), 319-325
- https://doi.org/10.1038/gene.2009.76
Abstract
The proinflammatory transcription factor nuclear factor-κB (NF-κB) has a central role in host defence against pneumococcal disease. Both rare mutations and common polymorphisms in the NFKBIA gene encoding the NF-κB inhibitor, IκB-α, associate with susceptibility to bacterial disease, but the possible role of polymorphisms within the related IκB-ζ gene NFKBIZ in the development of invasive pneumococcal disease (IPD) has not been reported previously. To investigate this further, we examined the frequencies of 22 single-nucleotide polymorphisms spanning NFKBIZ in two case–control studies, comprising UK Caucasian (n=1008) and Kenyan (n=723) individuals. Nine polymorphisms within a single UK linkage disequilibrium (LD) block and all four polymorphisms within the equivalent, shorter Kenyan LD block displayed either a significant association with IPD or a trend towards association. For each polymorphism, heterozygosity was associated with protection from IPD when compared with the combined homozygous states (for example, for rs600718, Mantel–Haenszel 2 × 2 χ2=7.576, P=0.006, odds ratio (OR)=0.67, 95% confidence interval (95% CI) for OR: 0.51–0.88; for rs616597, Mantel–Haenszel 2 × 2 χ2=8.715, P=0.003, OR=0.65, 95% CI: 0.49–0.86). We conclude that multiple NFKBIZ polymorphisms associate with susceptibility to IPD in humans. The study of multiple populations may aid in fine mapping of associations within extensive regions of strong LD (‘transethnic mapping’).Keywords
This publication has 37 references indexed in Scilit:
- Interleukin-17A Mediates Acquired Immunity to Pneumococcal ColonizationPLoS Pathogens, 2008
- The Nuclear IκB Protein IκBζ Specifically Binds NF-κB p50 Homodimers and Forms a Ternary Complex on κB DNAJournal of Molecular Biology, 2008
- Requirements for Two Proximal NF-κB Binding Sites and IκB-ζ in IL-17A-induced Human β-Defensin 2 Expression by Conducting Airway EpitheliumJournal of Biological Chemistry, 2008
- Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controlsNature, 2007
- Replicating genotype–phenotype associationsNature, 2007
- A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosisNature Genetics, 2007
- Haploview: analysis and visualization of LD and haplotype mapsBioinformatics, 2004
- Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IκBζNature, 2004
- Streptococcus pneumoniae colonisation: the key to pneumococcal diseaseThe Lancet Infectious Diseases, 2004
- THE NF-κB AND IκB PROTEINS: New Discoveries and InsightsAnnual Review of Immunology, 1996