A Novel SLPI 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 <i>SLPI</i> 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 <i>SLPI</i> was observed in saliva RNA of variant carriers. In bulk mRNA-seq data from an independent cohort of children with otitis media, <i>SLPI</i> was co-expressed with genes involved in infection, immune response, inflammation, and epithelial cell organization. After inoculation of non-typeable <i>Haemophilus influenzae</i>, <i>Slpi</i> was upregulated in polymorphonuclear leukocytes and epithelial cells of mouse middle ears. Furthermore, in the human middle ear, <i>Haemophilus</i> was significantly enriched in non-carriers, whereas <i>Family-XI-Incertae-Sedis</i> and <i>Dialister</i> were significantly enriched in variant carriers. Given the role of SLPI in immune modulation and host defense in mucosal epithelia, our findings support the <i>SLPI</i> variant as modulating susceptibility to otitis media.