학술논문
Multi-omic studies on missense PLG variants in families with otitis media.
Document Type
Article
Author
Bootpetch, Tori C.; Hafrén, Lena; Elling, Christina L.; Baschal, Erin E.; Manichaikul, Ani W.; Pine, Harold S.; Szeremeta, Wasyl; Scholes, Melissa A.; Cass, Stephen P.; Larson, Eric D.; Chan, Kenny H.; Ishaq, Rafaqat; Prager, Jeremy D.; Shaikh, Rehan S.; Gubbels, Samuel P.; Yousaf, Ayesha; University of Washington Center for Mendelian Genomics (UW-CMG); Bamshad, Michael J.; Nickerson, Deborah A.; Leal, Suzanne M.
Source
Subject
*OTITIS media
*MIDDLE ear diseases
*MEDICAL genetics
*PLASMINOGEN
*EXOMES
*MISSENSE mutation
*RNA sequencing
*MOLECULAR models
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Language
ISSN
2045-2322
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. [ABSTRACT FROM AUTHOR]