There is a clear hereditary component in allergic rhinitis that has been well corroborated by segregation studies and investigations in twins [
19,
20]. However, much less evidence exists on inheritage of NAR [
21] and of CRS [
22]. Genome-wide association studies (GWAS) have reported 22 significant AR-associating loci [
23,
24,
25•,
26•,
27]. Based on our unpublished results of RNA-sequencing for nasal brushings, less than half of these loci could have epithelial function. Yet, their role in the epithelium and other cell types during the development of AR has not been resolved. As an example, FOXA1 (25) is connected to cell differentiation. It can increase the expression of mucin 2 gene in goblet cells [
28]. TPD52 [
25•] is expressed predominantly by epithelial cells and has a function in the development or maintenance of the epithelial cell phenotype, in cell proliferation, migration, and cell death [
29]. ID2 [
25•] binds TGF-β and takes part in cell differentiation, apoptosis, and epithelial to mesenchymal transition [
30]. IL4R [
25•] has a role in the regeneration and in enhancing MUC4 in respiratory epithelium. It binds IL4 and IL13, which promote IgE production and differentiation of Th2 cells [
31]. ETS1 [
25•] is a transcription factor particularly expressed in basal cells of airway epithelium. It is important in stem cell development, cell senescence, and death [
32]. TLR1-TLR6-TLR10 [
25•] and NOD1 [
23] are pattern recognition receptors found in nasal epithelium [
33]. Interestingly, Nilsson et al. performed a replication study in children with AR and showed that TLR6-TLR1 locus is likely to have a central role in the development of allergic disease [
34]. Still, further studies are needed to show, whether these AR-associating loci are important in epithelial pathology during airway allergy.
Bunyavanich et al. studied further the biologic context for AR-associating loci identified by GWAS, by expression quantitative trait loci (eQTL) and expression single nucleotide polymorphism (eSNP) mapping, as well as by network and pathway analyses [
26•]. Interestingly, they recognized enrichment in mitochondrial pathways [
26•]. Previous studies have detected the mitochondrial dysfunction of airway epithelium during bacterial and viral infections, cigarette smoking, and asthma [
35].
Two pooling-based GWASes are known for the CRS phenotype. A study discovered three loci that consistently associate with CRS, yet their function in sinonasal epithelium is not confirmed: TCF7L2 [
36] participates in the Wnt signaling pathway and modulates MYC expression. It maintains the epithelial stem cell compartment of the small intestine. AOAH [
36] has been replicated significantly in a Chinese population [
37]. It is expressed in epithelium and leukocytes. It detoxifies gram-negative bacteria by hydrolyzing acyloxylacyl-linked fatty acyl chains of lipopolysaccharides. TP73 [
38] mediates oxidative stress response, cell differentiation, and remodeling in nasal polyp epithelium [
39]. The group of Desrosiers performed also RNA array analysis and detected upregulation of the expression of the LAMB1 gene and the laminin pathway, in differentiated primary epithelial cells from CRS patients, suggesting a role for extracellular matrix genes in the development of CRS [
40]. To the knowledge of the authors, there are no GWAS studies on NAR phenotypes.
The Interplay Between Inhaled Particles and Epithelial Transcriptome
A great variety of allergen-, host-, and environment-dependent mechanisms facilitates allergen and pathogen entry into the respiratory mucosa. Allergens have proteolytic, lipid-binding, and microbial-mimicking properties which enable their entry [
41]. Penetration of mite allergens, for instance, associates with aberrant host functions such as pattern recognition, calcium metabolism, and cell-cell contacts [
42,
43•,
44,
45]. We have demonstrated by electron microscopy and proteomics that birch pollen allergens (Bet v1) were able to bind plasma membrane lipid rafts and were rapidly transported through the epithelium in caveolar vesicles to meet a mast cell solely in patients allergic to birch [
46]. Microarray experiments have shown that pollen exposure causes greatest fold changes in the nasal epithelial transcripts that belong to immunology category in controls, whereas response to virus and cellular transportation are abundant categories in pollen allergic subjects [
15,
47].
We performed RNA microarray of cultured epithelial cells from bronchial brushings and nasal biopsies and showed that about 2000 genes were differentially expressed between healthy lower and upper airway epithelium, whereas in allergic rhinitis with or without asthma, this was only 40 and 301 genes, respectively. Genes influenced by allergic rhinitis with or without asthma were linked to lung development, remodeling, regulation of peptidases, and normal epithelial barrier functions [
48]. We also stimulated primary nasal and bronchial epithelial cells from the same individuals by a viral double-stranded RNA (dsRNA) analog poly (I:C) and identified gene expression profiles by RNA-array analysis. Asthma patients demonstrated significantly fewer induced genes, exhibiting reduced downregulation of mitochondrial genes. The majority of genes related to viral responses appeared to be similarly induced in upper and lower airways in all groups. However, the induction of several interferon-related genes was impaired in patients with asthma [
48]. Interestingly, expression profiling showed resemblance in the cytokine profiles of EGR1, DUSP1, FOSL1, JUN, MYC, and IL6 after stimulation of airway epithelial cells with either dsRNA or with house dust mite; however, both triggers also induced a specific response (e.g., ATF3, FOS, and NFKB1) [
49•]. This and other studies suggest that the risk for microbial infection and its underlying immune dysfunction might be a phenotypic or clinical feature of both atopic and nonatopic chronic conditions in the airways than only a secondary effect [
5].
Modulation of Transcriptome in Upper Airway Epithelium
There are several molecular mechanisms by which environmental factors might regulate gene expression. Epigenetic mechanisms alter gene expression without altering the underlying DNA sequence [
50]. The most studied epigenetic mechanisms are DNA methylation and histone modifications. Early infections together with other factors may shape developing immunity via epigenetic programming, which is partly inherited [
51,
52]. Buro-Auriemma et al. showed that cigarette smoking induces small airway epithelial epigenetic changes with corresponding modulation of gene expression [
53]. So far, epithelial epigenetics in upper airways have not been studied on systems level.
Recent genome-wide studies confirm that much of the DNA that does not encode proteins encode various types of functional RNAs, which are important players in gene regulation. MicroRNAs (miRNA) are small noncoding RNAs and important fine tuners of immune systems [
54]. By binding to its target transcripts, miRNA is able to decrease translation [
54]. Rager performed RT-PCR on nasal epithelial samples from macaques that inhaled formaldehyde and detected significant modification in miRNA expression profiles, which influence apoptosis signaling [
55]. McKiernan examined long noncoding RNA transcripts (lncRNAs) from bronchial brushings by microarray analysis and found that 1063 out of over 30,000 lncRNAs had different expression between cystic fibrosis and noncystic fibrosis individuals [
56]. Thus, it seems that pathologic processes in the airway epithelium are partly driven by noncoding RNAs, which might alter the regulation of gene expression.