br Patients and Methods br Results br

Patients and Methods
Results
Discussion In this study of children with invasive bacterial disease, we found an association between a polymorphism in the NFKBIE gene and increased susceptibility to IPD. This association was specific for the risk of pneumococcal meningitis. A number of other previously described associations between IPD and the SNPs, mainly in adults, were not replicated in our population of children. We did not find an association between any of the SNPs and IMD, neither with an increased risk for 30-day mortality after IPD or IMD. The pathogenesis and pathophysiology of bacterial meningitis involve a complex interplay between virulence factors characterizing the pathogens and the host immune response. The exact role of NFKBIE in this process is unknown, but our findings may suggest that IκB-ε is of greater importance in more disseminated infections, compared to the other IκB inhibitor proteins included in this study. Our inability to replicate the results in our bacteremia population may suggest that the host defense against pathogens crossing the blood–brain barrier is compromised in patients carrying a NFKBIE polymorphism. We chose to include children <5years in order to create a homogeneous population. It has been suggested that severe primary infections in childhood are more likely a result of single-gene variations compared to more complex genetics in adults (Alcaïs et al., 2010), which also makes genetic predisposition to infectious diseases particularly interesting in pediatric populations. In a Caucasian population aged 0–94years (mean 59years) Chapman et al. demonstrated that polymorphisms in the NFKBIE SNP were associated with protection from IPD but not pneumococcal empyema (Chapman et al., 2007). Heterozygotes tended to have increased susceptibility to pneumococcal empyema. However, this association was not significant when analyzed with logistic regression using a ibuprofen msds model (Chapman et al., 2007). In our population we were not able to replicate the finding that mutant allele carriers were protected from IPD. However, our results are similar to Chapman\'s findings in the sense that empyema is more invasive than bacteremia. This may support our hypothesis, that NFKBIE is important in invasive disease. Furthermore, bacteremia and meningitis are two different manifestations of pneumococcal disease, and the frequency of each serotype varies in these two patient groups. This might also be reflected in our results of the NFKBIE SNP. Although there was no significant association with IPD for the two adjacent NFKBIA polymorphisms, a possible trend towards increased susceptibility for mutant allele carriers appeared in the small subgroup of children with multiple IPD episodes. The NFKBIA polymorphisms were associated significantly with recurrent IPD at the 0.05 significance level, but lost significance when adjusted for multiple comparisons according to the Bonferroni method. This finding sets the stage for further investigation in a larger study population. However, since recurrent IPD is a rare condition, it may be challenging to include a sufficient number of patients in a future study. The interaction between NFKBIA and NFKBIE may be important, because the two genes probably have similar functions in determining susceptibility to IPD (Chapman et al., 2007, 2010a). In contrast to mutations in monogenic diseases most disease-associated polymorphisms in complex diseases have moderate effects on disease susceptibility, and hundreds or thousands of loci may contribute to subjects\' increased risk (Gibson, 2011). This could be one reason why we did not find an association between NFKBIA SNPs and IPD. We cannot rule out that an even larger study could demonstrate a relatively small effect of a single SNP. A potential limitation in this study would be that we assume that cases were healthy prior to invasive disease. As described by Gaschignard et al. some of these children might have unidentified immunodeficiencies or other chronic diseases that have not been diagnosed at the time of IPD (Gaschignard et al., 2014), and the same might occur for the IMD cases.