Acute otitis media and otitis media with effusion are common childhood disorders, a source of significant morbidity, and a leading cause of antibiotic prescription in primary health care. Although effective treatments are available, some shortcomings remain, and thus better treatments would be welcome. Recent discoveries within the field of otitis media research relating to its etiology and pathogenesis have led to further investigation aimed at developing novel treatments. This article provides a review of the latest evidence relating to the understanding of acute otitis media and otitis media with effusion, current treatment strategies, their limitations, new areas of research, and novel strategies for treatment.

/pdf/update-on-otitis-media-prevention-and-treatment-2s4yqobi4t.pdf

Update on otitis media – prevention and treatment

C57. American Society for Microbiology Washington, DC p.45. 56. Fennoll A, Bourgon CM, Munoz R, et al. Serotype distribution and antimicrobial resistance of Streptococcus pneumoniae isolates causing systemic infections in Spain, 1979–1989. Rev Infect Dis 1991;

Otitis media in infants and children.

© 2015 Hafren et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Predisposition to childhood otitis media (OM) has a strong genetic component, with polymorphisms in innate immunity genes suspected to contribute to risk. Studies on several genes have been conducted, but most associations have failed to replicate in independent cohorts. Methods We investigated 53 gene polymorphisms in a Finnish cohort of 624 cases and 778 controls. A positive association signal was followed up in a tagging approach and tested in an independent Finnish cohort of 205 cases, in a British cohort of 1269 trios, as well as in two cohorts from the United States (US); one with 403 families and the other with 100 cases and 104 controls. Results In the initial Finnish cohort, the SNP rs5030717 in the TLR4 gene region showed significant association (OR 1.33, P = .003) to OM. Tagging SNP analysis of the gene found rs1329060 (OR 1.33, P = .002) and rs1329057 (OR 1.29, P = .003) also to be associated. In the more severe phenotype the association was stronger. This finding was supported by an independent Finnish case cohort, but the associations failed to replicate in the British and US cohorts. In studies on TLR4 signaling in 20 study subjects, the three-marker risk haplotype correlated with a decreased TNFa secretion in myeloid dendritic cells. Conclusions The TLR4 gene locus, regulating the innate immune response, influences the genetic predisposition to childhood OM in a subpopulation of patients. Environmental factors likely modulate the genetic components contributing to the risk of OM.

/pdf/predisposition-to-childhood-otitis-media-and-genetic-4t8la2647q.pdf

Predisposition to Childhood Otitis Media and Genetic Polymorphisms within the Toll-Like Receptor 4 (TLR4) Locus

Polymorphisms in Toll-like receptors 2 and 4 genes and their expression in chronic suppurative otitis media

Otitis media with effusion (OME) is the most common cause of hearing loss in children, and tympanostomy (ear tube insertion) to alleviate the condition remains the commonest surgical intervention in children in the developed world. Chronic and recurrent forms of otitis media (OM) are known to have a very substantial genetic component; however, until recently, little was known of the underlying genes involved. The Jeff mouse mutant carries a mutation in the Fbxo11 gene, a member of the F-box family, and develops deafness due to a chronic proliferative OM. We previously reported that Fbxo11 is involved in the regulation of transforming growth factor beta (TGF-β) signalling by regulating the levels of phospho-Smad2 in the epithelial cells of palatal shelves, eyelids and airways of the lungs. It has been proposed that FBXO11 regulates the cell's response to TGF-β through the ubiquitination of CDT2. Additional substrates for FBXO11 have been identified, including p53. Here, we have studied both the genetic and biochemical interactions between FBXO11 and p53 in order to better understand the function of FBXO11 in epithelial development and its potential role in OM. In mice, we show that p53 (also known as Tp53) homozygous mutants and double heterozygous mutants (Jf/+ p53/+) exhibit similar epithelial developmental defects to Fbxo11 homozygotes. FBXO11 and p53 interact in the embryonic lung, and mutation in Fbxo11 prevents the interaction with p53. Both p53 and double mutants show raised levels of pSMAD2, recapitulating that seen in Fbxo11 homozygotes. Overall, our results support the conclusion that FBXO11 regulates the TGF-β pathway in the embryonic lung via cross-talk with p53.

/pdf/interactions-between-the-otitis-media-gene-fbxo11-and-p53-in-3yp28wbi1k.pdf

Interactions between the otitis media gene, Fbxo11, and p53 in the mouse embryonic lung.

Objectives/Hypothesis

The genetic factors leading to a predisposition to otitis media are not well understood. The objective of the current study was to develop a tag-single nucleotide polymorphism (SNP) panel to determine if there is an association between candidate gene polymorphisms and the development of chronic otitis media with effusion.



Study Design

A 1:1 case/control design of 100 cases and 100 controls was used. The study was limited to the chronic otitis media with effusion phenotype to increase the population homogeneity.



Methods

A panel of 192 tag-SNPs was selected. Saliva for DNA extraction was collected from 100 chronic otitis media with effusion cases and 100 controls. After quality control, 100 case and 79 control samples were available for hybridization. Genomic DNA from each subject was hybridized to the SNP probes, and genotypes were generated. Quality control across all samples and SNPs reduced the final SNPs used for analysis to 170. Each SNP was then analyzed for statistical association with chronic otitis media with effusion.



Results

Eight SNPs from four genes had an unadjusted P value of <.05 for association with the chronic otitis media with effusion phenotype (TLR4, MUC5B, SMAD2, SMAD4); five of these polymorphisms were in the TLR4 gene.



Conclusions

Even though these results need to be replicated in a novel population, the presence of five SNPs in the TLR4 gene having association with chronic otitis media with effusion in our study population lends evidence for the possible role of this gene in the susceptibility to otitis media.



Level of Evidence

NA. Laryngoscope, 124:1229–1235, 2014

Genetic susceptibility to chronic otitis media with effusion: candidate gene single nucleotide polymorphisms.

Patients with chronic obstructive pulmonary disease (COPD) are still waiting for curative treatments. For these to be developed, better understanding of molecular mechanisms driving disease onset is required. Considering the environmental cause of COPD, we hypothesized that the disease will be associated with altered epigenetic signalling in lung cells. Using whole-genome bisulfite sequencing, we generated genome-wide DNA methylation maps at single CpG resolution of parenchymal fibroblasts and alveolar type 2 (AT2) cells across COPD stages. We demonstrate that epigenetic landscape is severely changed in COPD, with epigenetics changes occurring predominantly in regulatory regions, including promoters and enhancers. RNA sequencing of matched samples showed dysregulation of pathways involved in proliferation, cell differentiation, extracellular matrix organisation, inflammation and viral immunity. Excitingly, we identify epigenetic changes and gene subsets dysregulated already in mild COPD, providing unique insight into early disease. Integration of profiling data identified epigenetically regulated pathways and candidate drivers of COPD phenotypes. We uncover a strong anticorrelation between gene expression and promoter methylation in AT2 cells, suggesting that aberrant transcriptional changes might be regulated by DNA methylation. Interferon (INF) signalling was the top upregulated pathway in AT2 cells with the strongest association to DNA methylation loss in the promoters of downstream genes. Using DNA methylation inhibitors and CRISPR-based epigenetic editing in lung cell lines we validated the link between methylation loss and activation of IFN-signalling. 

High-resolution transcriptomic and epigenetic profiling across disease stages identifies novel regulators of COPD phenotypes.

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Genetic susceptibility to chronic otitis media with effusion: candidate gene single nucleotide polymorphisms.

High-resolution transcriptomic and epigenetic profiling across disease stages identifies novel regulators of COPD phenotypes.