A Novel Splice Variant Confers Susceptibility to Otitis Media in Humans.

Otitis media is the most frequently diagnosed disease and a leading cause of hearing loss in young children. However, genetic contributors to susceptibility and pathogen-host-environment interactions in otitis media remain to be identified. Such knowledge would help identify at-risk individuals and effectively monitor, diagnose, and treat patients with otitis media. Through exome and Sanger sequencing, we identified a rare, deleterious splice variant c.394+1G>T co-segregating with otitis media in a large pedigree, with a genome-wide significant maximum LOD score of 4.59. Alternative splicing of was observed in saliva RNA of variant carriers. In bulk mRNA-seq data from an independent cohort of children with otitis media, was co-expressed with genes involved in infection, immune response, inflammation, and epithelial cell organization. After inoculation of non-typeable , was upregulated in polymorphonuclear leukocytes and epithelial cells of mouse middle ears. Furthermore, in the human middle ear, was significantly enriched in non-carriers, whereas and were significantly enriched in variant carriers. Given the role of SLPI in immune modulation and host defense in mucosal epithelia, our findings support the variant as modulating susceptibility to otitis media.