Rationale: Increasing evidence supports a key role for the transcription factor nuclear factor (NF)-?B in the host response to pneumococcal infection. Control of NF-?B activity is achieved through interactions with the I?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?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 × 2 ?^sup 2^ = 13.030, p = 0.0003; odds ratio [OR], 0.60; 95% confidence interval [CI], 0.45-0.79; rs2233406: Mantel-Haenszel 2 × 2 ?^sup 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-B therefore not only causes a very rare immunodeficiency state but may also influence the development of common infectious disease.
Infection with Streptococcus pneumoniae remains a significant global problem, accounting for the deaths of more than 1 million children younger than 5 years worldwide (1). Invasive pneumococcal disease (IPD) is defined by the isolation of S. pneumoniae from a normally sterile site, such as blood (septicemia), cerebrospinal fluid (meningitis), or pleural fluid (thoracic empyema). The incidence rate of IPD ranges from 10 to 100 per 100,000 persons per year, and despite advances in medical treatments, the mortality rate of IPD in adults remains at least 10 to 20% (1). Colonization of the nasopharynx by the pneumococcus is widespread, yet only a minority of individuals develop invasive disease (2). An important, and often neglected, factor that influences the development of infectious diseases such as IPD is the host’s genetic profile (3).
The ubiquitous transcription factor nuclear factor (NF)-?B is central to a diverse array of cellular processes, including host innate and adaptive immune responses (4, 5). Activation of NF-B occurs after stimulation of a variety of immune receptors, including Toll-like receptors (TLRs) and members of the interleukin (IL)-1 and tumor necrosis factor receptor superfamilies. The signaling pathway downstream of the TLR and IL-1 family of receptors is complex and incompletely understood; key mediators include the cytoplasmic adaptor molecules MyD88 and Mal/TIRAP, which activate TRAF6 via IL-1 receptorassociated kinases (IRAK1 and IRAK4) (6, 7). In unstimulated cells,NF-?Btranscription factors are prevented frombindingDNA due to their association with the inhibitors of NF-?B (I?B) protein family; phosphorylation of the I?B inhibitors by the I?B kinase complex leads ultimately to their degradation and the release of NF-?B, which is then capable of inducing gene transcription (5, 8). The best-studied members of the I?B family are I?B-?, I?B-?, and I?B-?, encoded by the genes NFKBIA (Chr14q13.2), NFKBIB (Chr19q13.2), and NFKBIE (Chr6p21.1), respectively (5). The recent identification of functional homologs of NF-?B and I?B in the horseshoe crab suggests that these components originatedmore than 500 million years ago and further underlines the key role of this pathway in host defense (9).
Although polymorphisms within genes encoding the activating TLRs have been associated with a number of disease states (10), the role of genetic variation within downstream components of the NF-?B pathway in disease development remains largely unexplored. Exceptions are the associations described between variants in NFKBIA with Crohn’s disease, trachoma, and sarcoidosis (11-13), and the recent association of a functional polymorphism in IRAK1 with outcomes from sepsis (14).
There is increasing evidence to support a critical role for the NF-?B pathway in the host immune response to pneumococcal infection. Many of the immune receptors capable of activating NF-?B are stimulated during pneumococcal infection, and, in particular, TLR2 recognizes components of gram-positive bacteria such as S. pneumoniae (15-17) and TLR4 recognizes the pneumococcal toxin pneumolysin (18). Activation of NF-B by pneumococci has been clearly demonstrated both in vitro and in animal models (19-22), and targeted genetic disruption of the NF-B p50 subunit in mice has been shown to increase susceptibility to overwhelming pneumococcal infection (23). Recently, two patients have been described with mutations in the NFKBIA gene leading to impaired NF-B activation and a primary immunodeficiency syndrome characterized by recurrent severe bacterial infections in association with the skin condition anhidrotic ectodermal dysplasia (24, 25). On the basis of these findings, we hypothesized that common polymorphisms in the I?B genes may be associated with susceptibility to the phenotype of IPD regularly encountered in clinical practice. To investigate this further, we studied the frequencies of polymorphisms in the three major I?B genes NFKBIA, NFKBIB, and NFKBIE in groups of individuals with IPD and thoracic empyema, as well as two control groups.