Common Genetic Polymorphisms within NFκB-Related Genes and the Risk of Developing Invasive Aspergillosis

Abstract

Invasive Aspergillosis (IA) is an opportunistic infection caused by Aspergillus, a ubiquitously present airborne pathogenic mold. A growing number of studies suggest a major host genetic component in disease susceptibility. Here, we evaluated whether 14 single-nucleotide polymorphisms within NFκB1, NFκB2, RelA, RelB, Rel, and IRF4 genes influence the risk of IA in a population of 834 high-risk patients (157 IA and 677 non-IA) recruited through a collaborative effort involving the aspBIOmics consortium and four European clinical institutions. No significant overall associations between selected SNPs and the risk of IA were found in this large cohort. Although a hematopoietic stem cell transplantation (HSCT)-stratified analysis revealed that carriers of the IRF4rs12203592T/T genotype had a six-fold increased risk of developing the infection when compared with those carrying the C allele (ORREC = 6.24, 95%CI 1.25–31.2, P = 0.026), the association of this variant with IA risk did not reach significance at experiment-wide significant threshold. In addition, we found an association of the IRF4AATC and IRF4GGTC haplotypes (not including the IRF4rs12203592T risk allele) with a decreased risk of IA but the magnitude of the association was similar to the one observed in the single-SNP analysis, which indicated that the haplotypic effect on IA risk was likely due to the IRF4rs12203592 SNP. Finally, no evidence of significant interactions among the genetic markers tested and the risk of IA was found. These results suggest that the SNPs on the studied genes do not have a clinically relevant impact on the risk of developing IA.

Massively parallel targeted resequencing reveals novel genetic variants associated with aspergillosis in paediatric patients with haematological malignancies

“…The five remaining genes included in our research (CCL2, CCR2, CD209, CLEC6A, CLEC6A) were previously subjected to case-control studies concerning aspergillosis. However, even the most comprehensive of those studies included only a limited number of the known SNPs [7].…”

“…As a result of those studies, a limited number of genetic polymorphisms were reported whose associations with aspergillosis were replicated and/or proved to have biological significance [reviewed in 6]. However, the majority of the studies concerning candidate genes concentrated on a limited number of single nucleotide polymorphisms (SNPs), employing low-or medium-throughput genotyping strategies [6,7,8].…”

Innate Lung Defense during Invasive Aspergillosis: New Mechanisms

“…In another study that focused specifically on recipients of solid-organ transplants, genome-wide association study analysis led to the identification of IL-1β and β-defensin 1 as essential for limiting fungal colonization and/or infection [69] . Finally, a recent study examining genes in the NF-κB family found that, despite identifying an SNP in IRF4 that was associated with a 6-fold increased risk of developing IA, this did not reach statistical significance [70] . Table 1 summarizes new findings in the area of innate host defense mechanisms during IA in the last 3-5 years.…”

Preparations for Invasion: Modulation of Host Lung Immunity During Pulmonary Aspergillosis by Gliotoxin and Other Fungal Secondary Metabolites

“…However, it should be indicated that it is not a trivial question to find out a concentration that inhibits NFkB activation and pro-inflammatory cytokine production in macrophages, independently of GT-mediated killing, at least in mouse macrophages (Unpublished data), which might affect the proper interpretation of these findings. However, the relevance of these findings in humans is not clear, since a recent study has shown that SNP in different molecules of NFkB pathway do not increase the risk of IA in SCT patients ( 91 ). Thus, in order to clarify the role of GT-mediated NFkB inhibition during IA, studies comparing NFkB activity during infection with GT producing and non-producing A. fumigatus strains should be carried out.…”