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However, genetic contributors to susceptibility and pathogen\u2013host\u2013environment 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&gt;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.<\/jats:p>","DOI":"10.3390\/ijms26041411","type":"journal-article","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T10:07:56Z","timestamp":1738922876000},"page":"1411","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Novel SLPI Splice Variant Confers Susceptibility to Otitis Media in Humans"],"prefix":"10.3390","volume":"26","author":[{"given":"Christina L.","family":"Elling","sequence":"first","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allen F.","family":"Ryan","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, School of Medicine and Veterans Affairs Medical Center, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Talitha Karisse L.","family":"Yarza","sequence":"additional","affiliation":[{"name":"Philippine National Ear Institute, National Institutes of Health, University of the Philippines Manila, Manila 1000, Philippines"},{"name":"Newborn Hearing Screening Reference Center, National Institutes of Health, University of the Philippines Manila, Manila 1000, Philippines"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amama","family":"Ghaffar","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erasmo Gonzalo d. 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Leah C.","family":"Tantoco","sequence":"additional","affiliation":[{"name":"Philippine National Ear Institute, National Institutes of Health, University of the Philippines Manila, Manila 1000, Philippines"},{"name":"Newborn Hearing Screening Reference Center, National Institutes of Health, University of the Philippines Manila, Manila 1000, Philippines"},{"name":"Department of Otolaryngology-Head and Neck Surgery, University of the Philippines College of Medicine\u2014Philippine General Hospital, Manila 1000, Philippines"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2914-4502","authenticated-orcid":false,"given":"Zubair M.","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abner L.","family":"Chan","sequence":"additional","affiliation":[{"name":"Philippine National Ear Institute, National Institutes of Health, University of the Philippines Manila, Manila 1000, Philippines"},{"name":"Newborn Hearing Screening Reference Center, National Institutes of Health, University of the Philippines Manila, Manila 1000, Philippines"},{"name":"Department of Otolaryngology-Head and Neck Surgery, University of the Philippines College of Medicine\u2014Philippine General Hospital, Manila 1000, Philippines"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel N.","family":"Frank","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlotte M.","family":"Chiong","sequence":"additional","affiliation":[{"name":"Philippine National Ear Institute, National Institutes of Health, University of the Philippines Manila, Manila 1000, Philippines"},{"name":"Newborn Hearing Screening Reference Center, National Institutes of Health, University of the Philippines Manila, Manila 1000, Philippines"},{"name":"Department of Otolaryngology-Head and Neck Surgery, University of the Philippines College of Medicine\u2014Philippine General Hospital, Manila 1000, Philippines"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Regie Lyn P.","family":"Santos-Cortez","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,7]]},"reference":[{"key":"ref_1","unstructured":"GBD 2019 Hearing Loss Collaborators (2021). 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