Dataset Information

Otitis media susceptibility and shifts in the head and neck microbiome due to SPINK5 variants.

ABSTRACT:

Background

Otitis media (OM) susceptibility has significant heritability; however, the role of rare variants in OM is mostly unknown. Our goal is to identify novel rare variants that confer OM susceptibility.

Methods

We performed exome and Sanger sequencing of >1000 DNA samples from 551 multiethnic families with OM and unrelated individuals, RNA-sequencing and microbiome sequencing and analyses of swabs from the outer ear, middle ear, nasopharynx and oral cavity. We also examined protein localisation and gene expression in infected and healthy middle ear tissues.

Results

A large, intermarried pedigree that includes 81 OM-affected and 53 unaffected individuals cosegregates two known rare A2ML1 variants, a common FUT2 variant and a rare, novel pathogenic variant c.1682A>G (p.Glu561Gly) within SPINK5 (LOD=4.09). Carriage of the SPINK5 missense variant resulted in increased relative abundance of Microbacteriaceae in the middle ear, along with occurrence of Microbacteriaceae in the outer ear and oral cavity but not the nasopharynx. Eight additional novel SPINK5 variants were identified in 12 families and individuals with OM. A role for SPINK5 in OM susceptibility is further supported by lower RNA counts in variant carriers, strong SPINK5 localisation in outer ear skin, faint localisation to middle ear mucosa and eardrum and increased SPINK5 expression in human cholesteatoma.

Conclusion

SPINK5 variants confer susceptibility to non-syndromic OM. These variants potentially contribute to middle ear pathology through breakdown of mucosal and epithelial barriers, immunodeficiency such as poor vaccination response, alteration of head and neck microbiota and facilitation of entry of opportunistic pathogens into the middle ear.

SUBMITTER: Frank DN

PROVIDER: S-EPMC8218788 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Publications

Otitis media susceptibility and shifts in the head and neck microbiome due to <i>SPINK5</i> variants.

Frank Daniel N DN Giese Arnaud P J APJ Hafren Lena L Bootpetch Tori C TC Yarza Talitha Karisse L TKL Steritz Matthew J MJ Pedro Melquiadesa M Labra Patrick John PJ Daly Kathleen A KA Tantoco Ma Leah C MLC Szeremeta Wasyl W Reyes-Quintos Maria Rina T MRT Ahankoob Niaz N Llanes Erasmo Gonzalo D V EGDV Pine Harold S HS Yousaf Sairah S Ir Diana D Einarsdottir Elisabet E de la Cruz Rhodieleen Anne R RAR Lee Nanette R NR Nonato Rachelle Marie A RMA Robertson Charles E CE Ong Kimberly Mae C KMC Magno Jose Pedrito M JPM Chiong Alessandra Nadine E ANE Espiritu-Chiong Ma Carmina MC San Agustin Maria Luz ML Cruz Teresa Luisa G TLG Abes Generoso T GT Bamshad Michael J MJ Cutiongco-de la Paz Eva Maria EM Kere Juha J Nickerson Deborah A DA Mohlke Karen L KL Riazuddin Saima S Chan Abner A Mattila Petri S PS Leal Suzanne M SM Ryan Allen F AF Ahmed Zubair M ZM Chonmaitree Tasnee T Sale Michele M MM Chiong Charlotte M CM Santos-Cortez Regie Lyn P RLP

Journal of medical genetics 20200724 7

<h4>Background</h4>Otitis media (OM) susceptibility has significant heritability; however, the role of rare variants in OM is mostly unknown. Our goal is to identify novel rare variants that confer OM susceptibility.<h4>Methods</h4>We performed exome and Sanger sequencing of >1000 DNA samples from 551 multiethnic families with OM and unrelated individuals, RNA-sequencing and microbiome sequencing and analyses of swabs from the outer ear, middle ear, nasopharynx and oral cavity. We also examined ...[more]

PMID: 32709676

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