. 2020 Sep 14;10(1):15035.

doi: 10.1038/s41598-020-70498-w.

Multi-omic studies on missense PLG variants in families with otitis media

Tori C Bootpetch¹, Lena Hafrén², Christina L Elling^{1

3}, Erin E Baschal¹, Ani W Manichaikul⁴, Harold S Pine⁵, Wasyl Szeremeta⁵, Melissa A Scholes^{1

6}, Stephen P Cass¹, Eric D Larson¹, Kenny H Chan^{1

6}, Rafaqat Ishaq⁷, Jeremy D Prager^{1

6}, Rehan S Shaikh⁷, Samuel P Gubbels¹, Ayesha Yousaf⁸; University of Washington Center for Mendelian Genomics (UW-CMG); Todd M Wine^{1

6}, Michael J Bamshad⁹, Patricia J Yoon^{1

6}, Herman A Jenkins¹, Deborah A Nickerson⁹, Sven-Olrik Streubel^{1

6}, Norman R Friedman^{1

6}, Daniel N Frank¹⁰, Elisabet Einarsdottir^{11

12}, Juha Kere^{11

12

13}, Saima Riazuddin⁷, Kathleen A Daly¹⁴, Suzanne M Leal¹⁵, Allen F Ryan¹⁶, Petri S Mattila², Zubair M Ahmed⁷, Michele M Sale^{4

17

18}, Tasnee Chonmaitree¹⁹, Regie Lyn P Santos-Cortez^{20

21}

Collaborators, Affiliations

Collaborators

University of Washington Center for Mendelian Genomics (UW-CMG):
Michael J Bamshad, Deborah A Nickerson, Suzanne M Leal

Affiliations

¹ Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
² Department of Otorhinolaryngology, Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
³ Human Medical Genetics and Genomics Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁴ Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville, VA, USA.
⁵ Department of Otolaryngology, University of Texas Medical Branch, Galveston, TX, USA.
⁶ Department of Pediatric Otolaryngology, Children's Hospital Colorado, Aurora, CO, USA.
⁷ Department of Otorhinolaryngology, Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA.
⁸ Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Punjab, Pakistan.
⁹ Department of Genome Sciences, University of Washington, Seattle, WA, USA.
¹⁰ Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹¹ Folkhälsan Institute of Genetics and Molecular Neurology Research Program, University of Helsinki, Helsinki, Finland.
¹² Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
¹³ Department of Medical and Molecular Genetics, King's College London, London, UK.
¹⁴ Department of Otolaryngology, Head and Neck Surgery, University of Minnesota, Minneapolis, MN, USA.
¹⁵ Department of Neurology, Center for Statistical Genetics, Gertrude H. Sergievsky Center, Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA.
¹⁶ Division of Otolaryngology, Department of Surgery, UCSD School of Medicine and VA Medical Center, La Jolla, CA, USA.
¹⁷ Department of Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, VA, USA.
¹⁸ Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Charlottesville, VA, USA.
¹⁹ Division of Infectious Diseases, Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, USA.
²⁰ Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. regie.santos-cortez@cuanschutz.edu.
²¹ Center for Children's Surgery, Children's Hospital Colorado, Aurora, CO, USA. regie.santos-cortez@cuanschutz.edu.

PMID: 32929111
PMCID: PMC7490366
DOI: 10.1038/s41598-020-70498-w

Multi-omic studies on missense PLG variants in families with otitis media

Tori C Bootpetch et al. Sci Rep. 2020.

. 2020 Sep 14;10(1):15035.

doi: 10.1038/s41598-020-70498-w.

Authors

Collaborators

University of Washington Center for Mendelian Genomics (UW-CMG):
Michael J Bamshad, Deborah A Nickerson, Suzanne M Leal

Affiliations

¹ Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
² Department of Otorhinolaryngology, Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
³ Human Medical Genetics and Genomics Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁴ Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville, VA, USA.
⁵ Department of Otolaryngology, University of Texas Medical Branch, Galveston, TX, USA.
⁶ Department of Pediatric Otolaryngology, Children's Hospital Colorado, Aurora, CO, USA.
⁷ Department of Otorhinolaryngology, Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA.
⁸ Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Punjab, Pakistan.
⁹ Department of Genome Sciences, University of Washington, Seattle, WA, USA.
¹⁰ Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹¹ Folkhälsan Institute of Genetics and Molecular Neurology Research Program, University of Helsinki, Helsinki, Finland.
¹² Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
¹³ Department of Medical and Molecular Genetics, King's College London, London, UK.
¹⁴ Department of Otolaryngology, Head and Neck Surgery, University of Minnesota, Minneapolis, MN, USA.
¹⁵ Department of Neurology, Center for Statistical Genetics, Gertrude H. Sergievsky Center, Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA.
¹⁶ Division of Otolaryngology, Department of Surgery, UCSD School of Medicine and VA Medical Center, La Jolla, CA, USA.
¹⁷ Department of Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, VA, USA.
¹⁸ Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Charlottesville, VA, USA.
¹⁹ Division of Infectious Diseases, Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, USA.
²⁰ Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. regie.santos-cortez@cuanschutz.edu.
²¹ Center for Children's Surgery, Children's Hospital Colorado, Aurora, CO, USA. regie.santos-cortez@cuanschutz.edu.

PMID: 32929111
PMCID: PMC7490366
DOI: 10.1038/s41598-020-70498-w

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.

PubMed Disclaimer

Conflict of interest statement

Dr. Allen Ryan is a co-founder of, shareholder in and uncompensated consultant to Otonomy, Inc., a relationship that was approved by the University of California San Diego. All other authors declare no competing interests.

Figures

**Figure 1**
Four multi-ethnic families with the *PLG* c.112A > G (p.Lys38Glu) and c.1414G > A (p.Asp472Asn) variants. Two Minnesota families (A) UMN48 and (B) UMN469 and (C) one Finnish trio UHF18 carry both variants with an autosomal dominant pattern of inheritance with reduced penetrance. (D) Despite Pakistani family PKOM18 being highly consanguineous, *PLG* c.1414G > A (p.Asp472Asn) co-segregated with OM in an autosomal dominant pattern.

**Figure 2**
Four multi-ethnic families with the *PLG* c.782G > A (p.Arg261His), c.2045 T > A (p.Ile682Asn) and c.1414G > A (p.Asp472Asn) variants. (A) In Minnesota family UMN5014a, the c.2045 T > A (p.Ile682Asn) variant co-segregates with OM, however two unaffected individuals carry the c.1414G > A (p.Asp472Asn) variant. (B) Three Finnish families have the c.782G > A (p.Arg261His) variant.

See this image and copyright information in PMC

References

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Multi-omic studies on missense PLG variants in families with otitis media

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Affiliations

Multi-omic studies on missense PLG variants in families with otitis media

Authors

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Abstract

Conflict of interest statement

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