Abstract
Otitis media (OM) is a common childhood disease characterised by middle ear inflammation following infection. Susceptibility to recurrent acute OM (rAOM) and chronic OM with effusion (COME) is highly heritable. Two murine mutants, Junbo and Jeff, spontaneously develop severe OM with similar phenotypes to human disease. Fine-mapping of these mutants identified two genes (Evi1 and Fbxo11) that interact with the transforming growth factor β (TGFβ) signalling pathway. We investigated these genes, as well as four Sma- and Mad-related (SMAD) genes of the TGFβ pathway, as candidate rAOM/COME susceptibility genes in two predominantly Caucasian populations. Single-nucleotide polymorphisms (SNPs) within FBXO11 (family-based association testing Z-Score=2.61; Pbest=0.009) were associated with severe OM in family-based analysis of 434 families (561 affected individuals) from the Western Australian Family Study of OM. The FBXO11 association was replicated by directed analysis of Illumina 660W-Quad Beadchip data available for 253 cases and 866 controls (OR=1.55 (95% CI 1.28–1.89); Pbest=6.9 × 10−6) available within the Western Australian Pregnancy Cohort (Raine) Study. Combined primary and replication results show Pcombined=2.98 × 10−6. Neither cohort showed an association with EVI1 variants. Family-based associations at SMAD2 (P=0.038) and SMAD4 (P=0.048) were not replicated. Together, these data provide strong evidence for FBXO11 as a susceptibility gene for severe OM.
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Acknowledgements
We thank all the families who have participated in the Western Australian Family Study of Otitis Media study and the Raine Study. We also thank the Raine Study Team for cohort coordination and data collection. This work was supported by funds to SEJ from a Raine Medical Research Foundation Priming Grant at the University of Western Australia (UWA) and a UWA Research Award and core funds to JMB from The Stan Perron Foundation, UWA and the Western Australian State Government. MSR is supported by an Australian Post Graduate Scholarship; SEJ is funded by a Brightspark Foundation (WA) Fellowship. The Raine Study has been supported by the NH&MRC over the last 20 years with funding for Core Management provided by UWA, The Raine Medical Research Foundation at UWA, the UWA Faculty of Medicine, Dentistry and Health Sciences, the Telethon Institute for Child Health Research and the Women and Infants Research Foundation. Raine Study Illumina 660W-Quad Beadchip Data was supported by NH&MRC (Palmer et al, ID 572613).
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Rye, M., Wiertsema, S., Scaman, E. et al. FBXO11, a regulator of the TGFβ pathway, is associated with severe otitis media in Western Australian children. Genes Immun 12, 352–359 (2011). https://doi.org/10.1038/gene.2011.2
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DOI: https://doi.org/10.1038/gene.2011.2
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