Chronic otitis media with effusion (COME) is the most common cause of hearing loss in children, and known to have high heritability. Mutant mouse models have identified Fbxo11, Evi1, Tgif1, and Nisch as potential risk loci. We recruited children aged 10 and under undergoing surgical treatment for COME from 35 hospitals in the UK, and their nuclear family. We performed association testing with the loci FBXO11, EVI1, TGIF1 and NISCH and sought to replicate significant results in a case-control cohort from Finland. We tested 1296 families (3828 individuals), and found strength of association with the T allele at rs881835 (p = 0.006, OR 1.39) and the G allele at rs1962914 (p = 0.007, OR 1.58) at TGIF1, and the A allele at rs10490302 (p = 0.016, OR 1.17) and the G allele at rs2537742 (p = 0.038, OR 1.16) at FBXO11. Results were not replicated. This study supports smaller studies that have also suggested association of otitis media with polymorphism at FBX011, but this is the first study to report association with the locus TGIF1. Both FBX011 and TGIF1 are involved in TGF-β signalling, suggesting this pathway may be important in the transition from acute to chronic middle ear inflammation, and a potential molecular target.

Chronic otitis media with effusion (COME) is the most common cause of childhood hearing loss in the developed world. Underlying pathophysiology is not well understood, and in particular the factors that lead to the transition from acute to chronic inflammation. Here we present the first genome-wide transcript analysis of white blood cells in the effusion of children with COME. Analysis of microarray data for enriched pathways reveals upregulation of hypoxia pathways, which is confirmed using real-time PCR and determining VEGF protein titres. Other pathways upregulated in both mucoid and serous effusions include Toll-like receptor signaling, complement, and RANK-RANKL. Cytology reveals neutrophils and macrophages predominated in both serous and mucoid effusions, however, serous samples had higher lymphocyte and eosinophil differential counts, while mucoid samples had higher neutrophil differential counts. Transcript analysis indicates serous fluids have CD4+ and CD8+ T-lymphocyte, and NK cell signatures. Overall, our findings suggest that inflammation and hypoxia pathways are important in the pathology of COME, and targets for potential therapeutic intervention, and that mucoid and serous COME may represent different immunological responses.

SummaryCollection of saliva for DNA extraction has created new opportunities to recruit participants from the community for genetic association studies. However, sample return rates are variable. No prior study has specifically addressed how study design impacts sample return. Using data from three large-scale genetic association studies we compared recruitment strategy and sample return rates. We found highly significant differences in sample return rates between the studies. In studies that recruited retrospectively, overall returns were much lower from families with a self-limiting condition who provided samples at a research centre or home visit, than adult elderly individuals with a chronic disease who provided samples by post (59% vs. 84%). Prospective recruitment was associated with high agreement to participate (72%), but subsequent low return of actual saliva samples (42%). A telephone call had marginal effect on recruitment in a retrospective family study, but significantly improved returns in a prospective family study. We found no effect upon DNA yield comparing observed versus unobserved sample collection, or between male and female adult participants. Overall, study design significantly impacts upon response rates for genetic association studies recruiting from the community. Our findings will help researchers in constructing and costing a recruitment protocol.