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Abstract
Otitis media (OM), a very common disease in young children, can result in hearing loss. In order to potentially replicate previously reported associations between OM and PLG, exome and Sanger sequencing, RNA-sequencing of saliva and middle ear samples, 16S rRNA sequencing, molecular modeling, and statistical analyses including transmission disequilibrium tests (TDT) were performed in a multi-ethnic cohort of 718 families and simplex cases with OM. We identified four rare PLG variants c.112A > G (p.Lys38Glu), c.782G > A (p.Arg261His), c.1481C > T (p.Ala494Val) and c.2045 T > A (p.Ile682Asn), and one common variant c.1414G > A (p.Asp472Asn). However TDT analyses for these PLG variants did not demonstrate association with OM in 314 families. Additionally PLG expression is very low or absent in normal or diseased middle ear in mouse and human, and salivary expression and microbial α-diversity were non-significant in c.1414G > A (p.Asp472Asn) carriers. Based on molecular modeling, the novel rare variants particularly c.782G > A (p.Arg261His) and c.2045 T > A (p.Ile682Asn) were predicted to affect protein structure. Exploration of other potential disease mechanisms will help elucidate how PLG contributes to OM susceptibility in humans. Our results underline the importance of following up findings from genome-wide association through replication studies, preferably using multi-omic datasets.
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1 University of Colorado Anschutz Medical Campus, Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Aurora, USA (GRID:grid.430503.1) (ISNI:0000 0001 0703 675X)
2 University of Helsinki and Helsinki University Hospital, Department of Otorhinolaryngology, Head and Neck Surgery, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071)
3 University of Colorado Anschutz Medical Campus, Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Aurora, USA (GRID:grid.430503.1) (ISNI:0000 0001 0703 675X); University of Colorado Anschutz Medical Campus, Human Medical Genetics and Genomics Program, Aurora, USA (GRID:grid.430503.1) (ISNI:0000 0001 0703 675X)
4 University of Virginia, Center for Public Health Genomics, School of Medicine, Charlottesville, USA (GRID:grid.27755.32) (ISNI:0000 0000 9136 933X)
5 University of Texas Medical Branch, Department of Otolaryngology, Galveston, USA (GRID:grid.176731.5) (ISNI:0000 0001 1547 9964)
6 University of Colorado Anschutz Medical Campus, Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Aurora, USA (GRID:grid.430503.1) (ISNI:0000 0001 0703 675X); Children’s Hospital Colorado, Department of Pediatric Otolaryngology, Aurora, USA (GRID:grid.413957.d) (ISNI:0000 0001 0690 7621)
7 University of Maryland, Department of Otorhinolaryngology, Head and Neck Surgery, School of Medicine, Baltimore, USA (GRID:grid.411024.2) (ISNI:0000 0001 2175 4264)
8 Bahauddin Zakariya University, Institute of Molecular Biology and Biotechnology, Multan, Pakistan (GRID:grid.411501.0) (ISNI:0000 0001 0228 333X)
9 University of Washington, Department of Genome Sciences, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657)
10 Columbia University Medical Center, Department of Neurology, Center for Statistical Genetics, Gertrude H. Sergievsky Center, Taub Institute for Alzheimer’s Disease and the Aging Brain, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675)
11 University of Colorado Anschutz Medical Campus, Division of Infectious Diseases, Department of Medicine, School of Medicine, Aurora, USA (GRID:grid.430503.1) (ISNI:0000 0001 0703 675X)
12 University of Helsinki, Folkhälsan Institute of Genetics and Molecular Neurology Research Program, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); Karolinska Institutet, Department of Biosciences and Nutrition, Huddinge, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626)
13 University of Helsinki, Folkhälsan Institute of Genetics and Molecular Neurology Research Program, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); Karolinska Institutet, Department of Biosciences and Nutrition, Huddinge, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626); King’s College London, Department of Medical and Molecular Genetics, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764)
14 University of Minnesota, Department of Otolaryngology, Head and Neck Surgery, Minneapolis, USA (GRID:grid.17635.36) (ISNI:0000000419368657)
15 UCSD School of Medicine and VA Medical Center, Division of Otolaryngology, Department of Surgery, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242)
16 University of Virginia, Center for Public Health Genomics, School of Medicine, Charlottesville, USA (GRID:grid.27755.32) (ISNI:0000 0000 9136 933X); University of Virginia, Department of Public Health Sciences, School of Medicine, Charlottesville, USA (GRID:grid.27755.32) (ISNI:0000 0000 9136 933X); University of Virginia, Department of Biochemistry and Molecular Genetics, School of Medicine, Charlottesville, USA (GRID:grid.27755.32) (ISNI:0000 0000 9136 933X)
17 University of Texas Medical Branch, Division of Infectious Diseases, Department of Pediatrics, Galveston, USA (GRID:grid.176731.5) (ISNI:0000 0001 1547 9964)
18 University of Colorado Anschutz Medical Campus, Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Aurora, USA (GRID:grid.430503.1) (ISNI:0000 0001 0703 675X); Children’s Hospital Colorado, Center for Children’s Surgery, Aurora, USA (GRID:grid.413957.d) (ISNI:0000 0001 0690 7621)