# A Novel SLPI Splice Variant Confers Susceptibility to Otitis Media in Humans

## TL;DR

A rare genetic variant in the SLPI gene increases susceptibility to otitis media, a common childhood ear infection linked to hearing loss.

## Contribution

A novel SLPI splice variant is identified as a genetic contributor to otitis media susceptibility through co-segregation and expression studies.

## Key findings

- A rare SLPI splice variant (c.394+1G>T) co-segregates with otitis media in a large family with genome-wide significant LOD score.
- SLPI is co-expressed with infection- and immunity-related genes in children with otitis media.
- SLPI expression increases in mouse middle ears after bacterial exposure, and guttural microbiome differences are observed between variant carriers and non-carriers.

## Abstract

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