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NFKBIZ polymorphisms and susceptibility to pneumococcal disease in European and African populations

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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References

  1. World Health Organisation. Pneumococcal vaccines. Wkly Epidemiol Record 2003; 14: 110–119.

    Google Scholar 

  2. Balakrishnan I, Crook P, Morris R, Gillespie SH . Early predictors of mortality in pneumococcal bacteraemia. J Infect 2000; 40: 256–261.

    Article  CAS  Google Scholar 

  3. Parsons HK, Dockrell DH . The burden of invasive pneumococcal disease and the potential for reduction by immunisation. Int J Antimicrob Agents 2002; 19: 85–93.

    Article  CAS  Google Scholar 

  4. Bogaert D, de Groot R, Hermans PWM . Streptococcus pneumoniae colonisation: the key to pneumococcal disease. Lancet Infect Dis 2004; 4: 144–154.

    Article  CAS  Google Scholar 

  5. Courtois G, Smahi A, Reichenbach J, Doffinger R, Cancrini C, Bonnet M et al. A hypermorphic IκBα mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. J Clin Invest 2003; 112: 1108–1115.

    Article  CAS  Google Scholar 

  6. Janssen R, van Wengen A, Hoeve MA, ten Dam M, van der Burg M, van Dongen J et al. The same IκBα mutation in two related individuals leads to completely different clinical syndromes. J Exp Med 2004; 200: 559–568.

    Article  CAS  Google Scholar 

  7. Schmeck B, Zahlten J, Moog K, van Laak V, Huber S, Hocke AC et al. Streptococcus pneumoniae-induced p38 MAPK-dependent phosphorylation of RelA at the interleukin-8 promoter. J Biol Chem 2004; 279: 53241–53247.

    Article  CAS  Google Scholar 

  8. Amory-Rivier CF, Mohler J, Bedos JP, Azoulay-Dupuis E, Henin D, Muffat-Joly M et al. Nuclear factor-kappaB activation in mouse lung lavage cells in response to Streptococcus pneumoniae pulmonary infection. Crit Care Med 2000; 28: 3249–3256.

    Article  CAS  Google Scholar 

  9. Jones MR, Simms BT, Lupa MM, Kogan MS, Mizgerd JP . Lung NF-κB activation and neutrophils recruitment require IL-1 and TNF receptor signaling during pneumococcal pneumonia. J Immunol 2005; 175: 7530–7535.

    Article  CAS  Google Scholar 

  10. Sha WC, Liou HC, Tuomanen EI, Baltimore D . Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses. Cell 1995; 80: 321–330.

    Article  CAS  Google Scholar 

  11. Baldwin AS . The NF-κB and IκB proteins: new discoveries and insights. Annu Rev Immunol 1996; 14: 649–681.

    Article  CAS  Google Scholar 

  12. Yamazaki S, Muta T, Takeshige K . A novel IκB protein, IκB-ζ, induced by proinflammatory stimuli, negatively regulates nuclear factor-κB in the nuclei. J Biol Chem 2001; 276: 27657–27662.

    Article  CAS  Google Scholar 

  13. Motoyama M, Yamazaki S, Eto-Kimura A, Takeshige K, Muta T . Positive and negative regulation of nuclear factor-κB-mediated transcription by IκB-ζ, an inducible nuclear protein. J Biol Chem 2005; 280: 7444–7451.

    Article  CAS  Google Scholar 

  14. Yamazaki S, Muta T, Matsuo S, Takeshige K . Stimulus-specific induction of a novel nuclear factor-κB regulator, IκB-ζ, via Toll/Interleukin-1 receptor is mediated by mRNA stabilization. J Biol Chem 2005; 280: 1678–1687.

    Article  CAS  Google Scholar 

  15. Yamamoto M, Yamazaki S, Uematsu S, Sato S, Hemmi H, Hoshino K et al. Regulation of Toll/Il-1-receptor-mediated gene expression by the inducible nuclear protein IκBζ. Nature 2004; 430: 218–222.

    Article  CAS  Google Scholar 

  16. Totzke G, Essmann F, Pohlmann S, Lindenblatt C, Jänicke RU, Schulze-Osthoff K . A novel member of the IkappaB family, human IkappaB-zeta, inhibits transactivation of p65 and its DNA binding. J Biol Chem 2006; 281: 12645–12654.

    Article  CAS  Google Scholar 

  17. Trinh DV, Zhu N, Farhang G, Kim BJ, Huxford T . The nuclear I kappaB protein I kappaB zeta specifically binds NF-kappaB p50 homodimers and forms a ternary complex on kappaB DNA. J Mol Biol 2008; 379: 122–135.

    Article  CAS  Google Scholar 

  18. Yamamoto M, Takeda K . Role of nuclear IkappaB proteins in the regulation of host immune responses. J Infect Chemother 2008; 14: 265–269.

    Article  CAS  Google Scholar 

  19. Chapman SJ, Khor CC, Vannberg FO, Frodsham A, Walley A, Maskell NA et al. IκB genetic polymorphisms and invasive pneumococcal disease. Am J Respir Crit Care Med 2007; 176: 181–187.

    Article  CAS  Google Scholar 

  20. Roy S, Knox K, Segal S, Griffiths D, Moore CE, Welsh KI et al. MBL genotype and risk of invasive pneumococcal disease: a case-control study. Lancet 2002; 359: 1569–1573.

    Article  CAS  Google Scholar 

  21. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007; 447: 661–678.

    Article  Google Scholar 

  22. Berkley JA, Lowe BS, Mwangi I, Williams T, Bauni E, Mwarumba S et al. Bacteremia among children admitted to a rural hospital in Kenya. N Engl J Med 2005; 352: 39–47.

    Article  CAS  Google Scholar 

  23. Jurinke C, van den Boom D, Cantor CR, Koster H . The use of MassARRAY technology for high throughput genotyping. Adv Biochem Eng Biotechnol 2002; 77: 57–74.

    CAS  PubMed  Google Scholar 

  24. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  Google Scholar 

  25. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B et al. The structure of haplotype blocks in the human genome. Science 2002; 296: 2225–2229.

    Article  CAS  Google Scholar 

  26. Todd JA . Statistical false positive or true disease pathway? Nat Genet 2006; 38: 731–733.

    Article  CAS  Google Scholar 

  27. Wall JD, Pritchard JK . Haplotype blocks and linkage disequilibrium in the human genome. Nat Rev Genet 2003; 4: 587–597.

    Article  CAS  Google Scholar 

  28. NCI-NHGRI Working Group on Replication in Association Studies. Replicating genotype-phenotype associations. Nature 2007; 447: 655–660.

    Article  Google Scholar 

  29. Dean M, Carrington M, O'Brien SJ . Balanced polymorphism selected by genetic versus infectious human disease. Annu Rev Genomics Hum Genet 2002; 3: 263–292.

    Article  CAS  Google Scholar 

  30. Mead S, Stumpf MP, Whitfield J, Beck JA, Poulter M, Campbell T et al. Balancing selection at the prion protein gene consistent with prehistoric kurulike epidemics. Science 2003; 300: 640–643.

    Article  CAS  Google Scholar 

  31. Carrington M, Nelson GW, Martin MP, Kissner T, Goedert JJ, Kaslow R et al. HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. Science 1999; 283: 1748–1752.

    Article  CAS  Google Scholar 

  32. Khor CC, Chapman SJ, Vannberg FO, Murphy C, Dunne A, Ling EY et al. A functional variant in MAL/TIRAP and protection against invasive pneumococcal disease, bacteraemia, malaria and tuberculosis. Nat Genet 2007; 39: 523–528.

    Article  CAS  Google Scholar 

  33. Ueta M, Hamuro J, Yamamoto M, Kaseda K, Akira S, Kinoshita S . Spontaneous ocular surface inflammation and goblet cell disappearance in IκBζ gene-disrupted mice. Invest Ophthalmol Vis Sci 2005; 46: 579–588.

    Article  Google Scholar 

  34. Lu YJ, Gross J, Bogaert D, Finn A, Bagrade L, Zhang Q et al. Interleukin-17A mediates acquired immunity to pneumococcal colonization. PLoS Pathog 2008; 4: e1000159.

    Article  Google Scholar 

  35. Lee HY, Andalibi A, Webster P, Moon SK, Teufert K, Kang SH et al. Antimicrobial activity of innate immune molecules against Streptococcus pneumoniae, Moraxella catarrhalis and nontypeable Haemophilus influenzae. BMC Infect Dis 2004; 4: 12.

    Article  Google Scholar 

  36. Kao CY, Kim C, Huang F, Wu R . Requirements for two proximal NF-kappaB binding sites and IkappaB-zeta in IL-17A-induced human beta-defensin 2 expression by conducting airway epithelium. J Biol Chem 2008; 283: 15309–15318.

    Article  CAS  Google Scholar 

  37. Aujla SJ, Dubin PJ, Kolls JK . Interleukin-17 in pulmonary host defense. Exp Lung Res 2007; 33: 507–518.

    Article  CAS  Google Scholar 

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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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Correspondence to S J Chapman.

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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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