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

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

doi:10.1136/jmedgenet-2020-106844

Cited by 18 publications

(12 citation statements)

References 48 publications

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“…Although the novel rare variants we identified might have potential effects on protein structure based on molecular modeling, PLG expression is very low or absent in normal or diseased middle ear tissues in both mouse and human. Our previous studies support a common mechanism by which the OM susceptibility variant affects expression of the encoded protein and other genes downstream, which in turn shifts the middle ear microbiome by changing the overall biodiversity or relative abundance of specific pathogens or commensal taxa 16,21,46,47 . The mostly negative results of our multiple studies showed that this disease mechanism does not apply to PLG variants in relation to OM susceptibility in humans.…”

Section: Discussionsupporting

confidence: 67%

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

Bootpetch

Hafrén

Elling

et al. 2020

Sci Rep

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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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Section: Discussionsupporting

confidence: 67%

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

Bootpetch

Hafrén

Elling

et al. 2020

Sci Rep

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“…In contrast, no differences in beta-diversity were observed in association with biological sex (p=0.20) or cephalosporin use (p=0.37). Only a few patients were positive for [a] use of local steroid as a component of antibiotic otic drops and [b] for FUT2 or SPINK5 variants ( Table 1 ), which we have previously shown to be determinants of ME microbiota ( Santos-Cortez et al., 2018 ; Frank et al., 2020 ; Elling et al., 2022 ); consequently, steroid use, FUT2 genotype, and SPINK5 genotype were excluded from all analyses.…”

Section: Resultsmentioning

confidence: 99%

“…Bacterial 16S rRNA genes were amplified from DNA samples using primers specific for the V1V2 region (27FYM 5’-AGAGTTTGATYMTGGCTCAG and 338R 5’-TGCTGCCTCCCGTAGGAGT), as previously described ( Santos-Cortez et al., 2018 ; Bootpetch et al., 2020 ; Frank et al., 2020 ). All work was performed in either a biosafety level 2 hood or a HEPA-filtered PCR hood following 15 minutes of ultraviolet irradiation.…”

Section: Methodsmentioning

confidence: 99%

Microbiota Associated With Cholesteatoma Tissue in Chronic Suppurative Otitis Media

Frank

Magno

Velasco

et al. 2022

Front. Cell. Infect. Microbiol.

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Otitis media (OM), defined as infection or inflammation of the middle ear (ME), remains a major public health problem worldwide. Cholesteatoma is a non-cancerous, cyst-like lesion in the ME that may be acquired due to chronic OM and cause disabling complications. Surgery is required for treatment, with high rates of recurrence. Current antibiotic treatments have been largely targeted to previous culturable bacteria, which may lead to antibiotic resistance or treatment failures. For this study, our goal was to determine the microbiota of cholesteatoma tissue in comparison with other ME tissues in patients with long-standing chronic OM. ME samples including cholesteatoma, granulation tissue, ME mucosa and discharge were collected from patients undergoing tympanomastoidectomy surgery for chronic OM. Bacteria were profiled by 16S rRNA gene sequencing in 103 ME samples from 53 patients. Respiratory viruses were also screened in 115 specimens from 45 patients. Differences in bacterial profiles (beta-diversity) and the relative abundances of individual taxa were observed between cholesteatoma and ME sample-types. Additionally, patient age was associated with differences in overall microbiota composition while numerous individual taxa were differentially abundant across age quartiles. No viruses were identified in screened ME samples. Biodiversity was moderately lower in cholesteatoma and ME discharge compared to ME mucosal tissues. We also present overall bacterial profiles of ME tissues by sample-type, age, cholesteatoma diagnosis and quinolone use, including prevalent bacterial taxa. Our findings will be useful for fine-tuning treatment protocols for cholesteatoma and chronic OM in settings with limited health care resources.

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“…Nasopharyngeal microbial composition differs between OM-prone and nonprone children [ 17 , 29 ]. Future studies could examine association between NREP and microbiomes of CSOM-prone Aboriginal children, complementing knowledge of rare variants at A2ML1 and SPINK5 and middle ear microbiomes in Filipino OM patients [ 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

Common and Rare Genetic Variants That Could Contribute to Severe Otitis Media in an Australian Aboriginal Population

Jamieson

Fakiola

Tang

et al. 2021

Clinical Infectious Diseases

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Background Our goal was to identify genetic risk factors for severe otitis media (OM) in Aboriginal Australians. Methods Illumina ® Omni2.5 BeadChip and imputed data were compared between 21 children with severe OM (multiple episodes chronic suppurative OM and/or perforations or tympanic sclerosis) and 370 individuals without this phenotype, followed by FUnctional Mapping and Annotation (FUMA). Exome data filtered for common (EXaC_all≥0.1) putative deleterious variants influencing protein coding (CADD-scaled scores ≥ 15) were used to compare 15 severe OM cases with 9 mild cases (single episode of acute OM recorded over ≥ 3 consecutive years). Rare (ExAC_all≤0.01) such variants were filtered for those present only in severe OM. Enrichr was used to determine enrichment of genes contributing to pathways/processes relevant to OM. Results FUMA analysis identified two plausible genetic risk loci for severe OM: NR3C1 (Pimputed_1000G=3.62x10 -6) encoding the glucocorticoid receptor, and NREP (Pimputed_1000G=3.67x10 -6) encoding neuronal regeneration related protein. Exome analysis showed: (i) association of severe OM with variants influencing protein coding (CADD-scaled ≥ 15) in a gene-set (GRXCR1, CDH23, LRP2, FAT4, ARSA, EYA4) enriched for Mammalian Phenotype Level 4 abnormal hair cell stereociliary bundle morphology and related phenotypes; (ii) rare variants influencing protein coding only seen in severe OM provided gene-sets enriched for “abnormal ear” (LMNA, CDH23, LRP2, MYO7A, FGFR1), integrin interactions, transforming growth factor signalling, and cell projection phenotypes including hair cell stereociliary bundles and cilium assembly. Conclusions This study highlights interacting genes and pathways related to cilium structure and function that may contribute to extreme susceptibility to OM in Aboriginal Australian children.

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

Cited by 18 publications

References 48 publications

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

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

Microbiota Associated With Cholesteatoma Tissue in Chronic Suppurative Otitis Media

Common and Rare Genetic Variants That Could Contribute to Severe Otitis Media in an Australian Aboriginal Population

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