A mouse-to-man candidate gene study identifies association of chronic otitis media with the loci TGIF1 and FBXO11

Abstract

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 is initiated by a bulla cavitation defect in the FBXO11 mouse model

“…Auditory-tube abnormalities were reported in newborn and adult Fbxo11 Jf/+ mice as well as the occurrence of scattered calcification of the bulla mucosa at 11 months of age (Hardisty et al, 2003). The other histopathological changes reported in this work, such as polyp formation, hyperplasia of ciliated epithelial cells and exudation into the bulla cavity, are common in chronic otitis media in mouse genetic models (Bhutta et al, 2017a,b). Thickening of the underlying bulla bone (osteosclerosis) (Hardisty et al, 2003) is a common response to injury and together these secondary changes do not suggest a specific initiating cause of otitis media.…”

“…FBXO11 is a candidate disease gene in human chronic otitis media with effusion (Segade et al, 2006; Rye et al, 2011a,b; Bhutta et al, 2017a,b; also see reviews by Rye et al, 2011a,b; Rye et al, 2012) and the Jeff ( Fbxo11 Jf/+ ) mutant mouse (Mouse Genome Informatics number 1862017) has conductive hearing loss and chronic otitis media (Hardisty et al, 2003; Hardisty-Hughes et al, 2006). FBXO11 is a member of the FBXO family of proteins that bind target proteins for ubiquitination and proteasomal degradation (Skaar et al, 2013; Cardozo and Pagano, 2004).…”

Understanding the aetiology and resolution of chronic otitis media from animal and human studies

“…The only OM association to have been replicated is at the FBXO11 locus. FBXO11 was initially associated with OM in an Australian cohort ( Rye et al, 2011 ), with nominal evidence of association, and then replicated in a UK cohort ( Bhutta et al, 2017 ) and a US cohort ( Segade et al, 2006 ), albeit at different polymorphisms at FBXO11 . Data from the Fbxo11 mouse model (see below) suggest that a mutation in Fbxo11 perturbs transforming growth factor (TGF)-β signalling in the middle ear.…”

Genomics of Otitis Media (OM): Molecular Genetics Approaches to Characterize Disease Pathophysiology

“…Using N-ethyl-N-nitrosourea mutagenesis, Crompton et al (2017) showed that the pathogenic variant, p.Leu972Pro, also known as edison variant, in the Nischarin (Nisch) gene leads to mild craniofacial defects, spontaneous OM by 20 weeks, and progressive hearing loss. Recent studies have reported the association of TGIF1 and NISCH loci as potential risk areas for OM in humans (Bhutta et al, 2017), thus supporting the relevance of knowledge obtained from mouse models to the pathophysiology of OM in humans.…”