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- Hirsch, S. D., et al.
(författare)
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The role of CDHR3 in susceptibility to otitis media
- 2021
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Ingår i: Journal of Molecular Medicine. - : Springer Nature. - 0946-2716 .- 1432-1440. ; 99:11, s. 1571-1583
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: Otitis media (OM) is common in young children and can cause hearing loss and speech, language, and developmental delays. OM has high heritability; however, little is known about OM-related molecular and genetic processes. CDHR3 was previously identified as a locus for OM susceptibility, but to date, studies have focused on how the CDHR3 p.Cys529Tyr variant increases epithelial binding of rhinovirus-C and risk for lung or sinus pathology. In order to further delineate a role for CDHR3 in OM, we performed the following: exome sequencing using DNA samples from OM-affected individuals from 257 multi-ethnic families; Sanger sequencing, logistic regression and transmission disequilibrium tests for 407 US trios or probands with OM; 16S rRNA sequencing and analysis for middle ear and nasopharyngeal samples; and single-cell RNA sequencing and differential expression analyses for mouse middle ear. From exome sequence data, we identified a novel pathogenic CDHR3 splice variant that co-segregates with OM in US and Finnish families. Additionally, a frameshift and six missense rare or low-frequency variants were identified in Finnish probands. In US probands, the CDHR3 p.Cys529Tyr variant was associated with the absence of middle ear fluid at surgery and also with increased relative abundance of Lysobacter in the nasopharynx and Streptomyces in the middle ear. Consistent with published data on airway epithelial cells and our RNA-sequence data from human middle ear tissues, Cdhr3 expression is restricted to ciliated epithelial cells of the middle ear and is downregulated after acute OM. Overall, these findings suggest a critical role for CDHR3 in OM susceptibility. Key messages: • Novel rare or low-frequency CDHR3 variants putatively confer risk for otitis media. • Pathogenic variant CDHR3 c.1653 + 3G > A was found in nine families with otitis media. • CDHR3 p.Cys529Tyr was associated with lack of effusion and bacterial otopathogens. • Cdhr3 expression was limited to ciliated epithelial cells in mouse middle ear. • Cdhr3 was downregulated 3 h after infection of mouse middle ear.
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- Bhutta, MF, et al.
(författare)
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A mouse-to-man candidate gene study identifies association of chronic otitis media with the loci TGIF1 and FBXO11
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 12496-
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Tidskriftsartikel (refereegranskat)abstract
- Chronic otitis media with effusion (COME) is the most common cause of hearing loss in children, and known to have high heritability. Mutant mouse models have identified Fbxo11, Evi1, Tgif1, and Nisch as potential risk loci. We recruited children aged 10 and under undergoing surgical treatment for COME from 35 hospitals in the UK, and their nuclear family. We performed association testing with the loci FBXO11, EVI1, TGIF1 and NISCH and sought to replicate significant results in a case-control cohort from Finland. We tested 1296 families (3828 individuals), and found strength of association with the T allele at rs881835 (p = 0.006, OR 1.39) and the G allele at rs1962914 (p = 0.007, OR 1.58) at TGIF1, and the A allele at rs10490302 (p = 0.016, OR 1.17) and the G allele at rs2537742 (p = 0.038, OR 1.16) at FBXO11. Results were not replicated. This study supports smaller studies that have also suggested association of otitis media with polymorphism at FBX011, but this is the first study to report association with the locus TGIF1. Both FBX011 and TGIF1 are involved in TGF-β signalling, suggesting this pathway may be important in the transition from acute to chronic middle ear inflammation, and a potential molecular target.
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- Bootpetch, TC, et al.
(författare)
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Multi-omic studies on missense PLG variants in families with otitis media
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 15035-
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Tidskriftsartikel (refereegranskat)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.
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- Einarsdottir, E, et al.
(författare)
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Genome-wide association analysis reveals variants on chromosome 19 that contribute to childhood risk of chronic otitis media with effusion
- 2016
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6, s. 33240-
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Tidskriftsartikel (refereegranskat)abstract
- To identify genetic risk factors of childhood otitis media (OM), a genome-wide association study was performed on Finnish subjects, 829 affected children, and 2118 randomly selected controls. The most significant and validated finding was an association with an 80 kb region on chromosome 19. It includes the variants rs16974263 (P = 1.77 × 10−7, OR = 1.59), rs268662 (P = 1.564 × 10−6, OR = 1.54), and rs4150992 (P = 3.37 × 10−6, OR = 1.52), and harbors the genes PLD3, SERTAD1, SERTAD3, HIPK4, PRX, and BLVRB, all in strong linkage disequilibrium. In a sub-phenotype analysis of the 512 patients with chronic otitis media with effusion, one marker reached genome-wide significance (rs16974263, P = 2.92 × 10−8). The association to this locus was confirmed but with an association signal in the opposite direction, in a UK family cohort of 4860 subjects (rs16974263, P = 3.21 × 10−4, OR = 0.72; rs4150992, P = 1.62 × 10−4, OR = 0.71). Thus we hypothesize that this region is important for COME risk in both the Finnish and UK populations, although the precise risk variants or haplotype background remain unclear. Our study suggests that the identified region on chromosome 19 includes a novel and previously uncharacterized risk locus for OM.
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- Frank, DN, et al.
(författare)
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Otitis media susceptibility and shifts in the head and neck microbiome due to SPINK5 variants
- 2021
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Ingår i: Journal of medical genetics. - : BMJ. - 1468-6244 .- 0022-2593. ; 58:7, s. 442-452
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Tidskriftsartikel (refereegranskat)abstract
- 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.MethodsWe 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.ResultsA 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.ConclusionSPINK5 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.
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| 7. |
- Hafren, L, et al.
(författare)
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Current knowledge of the genetics of otitis media
- 2012
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Ingår i: Current allergy and asthma reports. - : Springer Science and Business Media LLC. - 1534-6315 .- 1529-7322. ; 12:6, s. 582-589
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Tidskriftsartikel (refereegranskat)
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| 8. |
- Hafren, L, et al.
(författare)
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Genetic background and the risk of otitis media
- 2012
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Ingår i: International journal of pediatric otorhinolaryngology. - : Elsevier BV. - 1872-8464 .- 0165-5876. ; 76:1, s. 41-44
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Tidskriftsartikel (refereegranskat)
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| 12. |
- Terashima, Noritsugu, et al.
(författare)
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Nondestructive analysis of lignin structure by NMR spectroscopy of specifically 13C-enriched lignins : Part 1. Solid state study of ginkgo wood
- 2002
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Ingår i: Holzforschung. - 0018-3830 .- 1437-434X. ; 56:1, s. 43-50
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Tidskriftsartikel (refereegranskat)abstract
- Guaiacyl-type lignin is the major component of ginkgo lignin. Specific 13c-enrichment of α, β and γ-carbons of the guaiacylpropane side chains was achieved by administration of coniferin-[α13C], coniferin-[β-13C] and coniferin-[γ13C], respectively, to growing stems of ginkgo trees. Unenriched coniferin was administered as a control. The xylem tissues containing specifically 13C-enriched lignins or unenriched lignin were subjected to analysis by solid state NMR. Subtraction of the spectrum of tissue containing unenriched lignin from the spectra of tissues containing 13C-enriched lignins gave difference spectra exclusively assigned to the enriched side chain carbons of intact protolignin in the cell walls. From the signal intensities determined under quantitative conditions and an estimate of corresponding standard uncertainties, the percentage ranges of the major inter-unit lignin bonds originating from the β-carbon of the coniferin precursor were estimated to be: β-O-4/α-O-R (R = H, polysaccharides or lignols) including β-OH, 53% to 57%; combined β-5, β-β and β-1, 32% to 36%; coniferaldehyde end groups, 2% to 4%; and coniferyl alcohol end groups, 4% to 6%.
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