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Published ahead of print on April 26, 2007, doi:10.1164/rccm.200702-169OC
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American Journal of Respiratory and Critical Care Medicine Vol 176. pp. 181-187, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200702-169OC

Original Article

I{kappa}B Genetic Polymorphisms and Invasive Pneumococcal Disease

Stephen J. Chapman1,2, Chiea C. Khor1, Fredrik O. Vannberg1, Angela Frodsham1, Andrew Walley1, Nicholas A. Maskell2, Christopher W. H. Davies3, Shelley Segal4, Catrin E. Moore4, Stephen H. Gillespie5, Paul Denny6, Nicholas P. Day7, Derrick W. Crook8, Robert J. O. Davies2 and Adrian V. S. Hill1

1 The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; 2 Oxford Centre for Respiratory Medicine, Churchill Hospital Site, Oxford Radcliffe Hospital, Oxford, United Kingdom; 3 Department of Respiratory Medicine, Royal Berkshire Hospital, Reading, United Kingdom; 4 Department of Paediatrics, John Radcliffe Hospital, Oxford, United Kingdom; 5 Centre for Medical Microbiology, Department of Infection, University College London, London, United Kingdom; 6 Medical Research Council UK Mouse Genome Centre and Mammalian Genetics Unit, Harwell, Oxon, United Kingdom; 7 Centre for Tropical Diseases, Cho Quan Hospital, Ho Chi Minh City, Vietnam; and 8 Department of Microbiology, John Radcliffe Hospital, Oxford, United Kingdom

Correspondence and requests for reprints should be addressed to Stephen J. Chapman, M.R.C.P., The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, UK. E-mail: schapman{at}well.ox.ac.uk

Rationale: Increasing evidence supports a key role for the transcription factor nuclear factor (NF)-{kappa}B in the host response to pneumococcal infection. Control of NF-{kappa}B activity is achieved through interactions with the I{kappa}B 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 I{kappa}B gene polymorphisms confer susceptibility to common bacterial disease.

Objectives: 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).

Measurements and Main 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 2 x 2 {chi}2 = 13.030, p = 0.0003; odds ratio [OR], 0.60; 95% confidence interval [CI], 0.45–0.79; rs2233406: Mantel-Haenszel 2 x 2 {chi}2 = 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-{kappa}B therefore not only causes a very rare immunodeficiency state but may also influence the development of common infectious disease.

Key Words: genetic polymorphisms • pneumococcal infection • nuclear factor-{kappa}B


AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject
The nuclear factor (NF)-{kappa}B inflammatory pathway plays a key role in the host immune response to pneumococcal infection, and very rare genetic mutations in an NF-{kappa}B inhibitor cause immunodeficiency with severe bacterial infection.

What This Study Adds to the Field
This study describes novel associations between common genetic polymorphisms in NF-{kappa}B inhibitors and susceptibility to invasive pneumococcal disease in humans.

 



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