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’).
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Acknowledgements
SJC is a Wellcome Trust Clinical Research Fellow; CCK is a scholar of the Agency for Science, Technology and Research (A-STAR), Singapore and member of the MBBS-PhD programme, Faculty of Medicine, National University of Singapore; AR is supported by the EU FP6 GRACE grant and the Academy of Finland; DWC is supported by the NIHR Biomedical Research Centre, Oxford; JAS is funded by the Wellcome Trust; TNW is funded by the Wellcome Trust, European Network 6 BioMalpar consortium Project and the MalariaGen Network funded by Bill and Melinda Gates; AVSH is a Wellcome Trust Principal Fellow. This paper is published with the permission of the director of the Kenya Medical Research Institute (KEMRI). This study was supported by the Wellcome Trust, United Kingdom.
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Chapman, S., Khor, C., Vannberg, F. et al. NFKBIZ polymorphisms and susceptibility to pneumococcal disease in European and African populations. Genes Immun 11, 319–325 (2010). https://doi.org/10.1038/gene.2009.76
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DOI: https://doi.org/10.1038/gene.2009.76
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