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

Daniel N. Frank, Arnaud P.J. Giese, Lena Hafren, Tori C. Bootpetch, Talitha Karisse L. Yarza, Matthew J. Steritz, Melquiadesa Pedro, Patrick John Labra, Kathleen A. Daly, Ma Leah C. Tantoco, Wasyl Szeremeta, Maria Rina T. Reyes-Quintos, Niaz Ahankoob, Erasmo Gonzalo D.V. Llanes, Harold S. Pine, Sairah Yousaf, Diana Ir, Elisabet Einarsdottir, Rhodieleen Anne R. De La Cruz, Nanette R. LeeRachelle Marie A. Nonato, Charles E. Robertson, Kimberly Mae C. Ong, Jose Pedrito M. Magno, Alessandra Nadine E. Chiong, Ma Carmina Espiritu-Chiong, Maria Luz San Agustin, Teresa Luisa G. Cruz, Generoso T. Abes, Michael J. Bamshad, Eva Maria Cutiongco-De La Paz, Juha Kere, Deborah A. Nickerson, Karen L. Mohlke, Saima Riazuddin, Abner Chan, Petri S. Mattila, Suzanne M. Leal, Allen F. Ryan, Zubair M. Ahmed, Tasnee Chonmaitree, Michele M. Sale, Charlotte M. Chiong, Regie Lyn P. Santos-Cortez

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)442-452
Number of pages11
JournalJournal of Medical Genetics
Issue number7
StatePublished - Jul 1 2021
Externally publishedYes


  • complex traits
  • genetic epidemiology
  • infection
  • infectious diseases
  • linkage

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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