Editorial: Otitis media susceptibility due to genetic variants.
Ontology highlight
ABSTRACT:
SUBMITTER: Marom T
PROVIDER: S-EPMC10752497 | biostudies-literature | 2023
REPOSITORIES: biostudies-literature
Publications
Editorial: Otitis media susceptibility due to genetic variants.
Marom Tal T Swords W Edward WE Santos-Cortez Regie Lyn P RLP
Frontiers in genetics 20231212
Similar Datasets
Project description:A duplication variant within the middle ear-specific gene A2ML1 cosegregates with otitis media in an indigenous Filipino pedigree (LOD score = 7.5 at reduced penetrance) and lies within a founder haplotype that is also shared by 3 otitis-prone European-American and Hispanic-American children but is absent in non-otitis-prone children and >62,000 next-generation sequences. We identified seven additional A2ML1 variants in six otitis-prone children. Collectively, our studies support a role for A2ML1 in the pathophysiology of otitis media.
| S-EPMC4528370 | biostudies-literature
Project description:Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154∗) is associated with either risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjects with otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c.604C>T (p.Arg202∗) variant co-segregates with otitis media in a Filipino pedigree (LOD = 4.0). Additionally, a rare variant, c.412C>T (p.Arg138Cys), is associated with recurrent/chronic otitis media in European-American children (p = 1.2 × 10-5) and US trios (TDT p = 0.01). The c.461G>A (p.Trp154∗) variant was also over-transmitted in US trios (TDT p = 0.01) and was associated with shifts in middle ear microbiota composition (PERMANOVA p < 10-7) and increased biodiversity. When all missense and nonsense variants identified in multi-ethnic US trios with CADD > 20 were combined, FUT2 variants were over-transmitted in trios (TDT p = 0.001). Fut2 is transiently upregulated in mouse middle ear after inoculation with non-typeable Haemophilus influenzae. Four FUT2 variants-namely p.Ala104Val, p.Arg138Cys, p.Trp154∗, and p.Arg202∗-reduced A antigen in mutant-transfected COS-7 cells, while the nonsense variants also reduced FUT2 protein levels. Common and rare FUT2 variants confer susceptibility to otitis media, likely by modifying the middle ear microbiome through regulation of A antigen levels in epithelial cells. Our families demonstrate marked intra-familial genetic heterogeneity, suggesting that multiple combinations of common and rare variants plus environmental factors influence the individual otitis media phenotype as a complex trait.
| S-EPMC6217759 | biostudies-literature
Project description:BackgroundOtitis 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.
| S-EPMC8218788 | biostudies-literature
Project description:Otitis Media Susceptibility and Middle Ear Microbial Shifts due to Gene Variants
| PRJNA593080 | ENA
Project description:Otitis Media Susceptibility and Middle Ear Microbial Shifts due to Gene Variants
| PRJNA593081 | ENA
Project description:The first Genome Wide Association Study (GWAS) of otitis media (OM) found evidence of association in the Western Australian Pregnancy Cohort (Raine) study, but lacked replication in an independent OM population. The aim of this study was to investigate association at these loci in our family-based sample of chronic otitis media with effusion and recurrent otitis media (COME/ROM). Autosomal SNPs were selected from the Raine OM GWAS results. SNPs from the Raine cohort GWAS genotyped in our GWAS of COME/ROM had P-values ranging from P = 0.06-0.80. After removal of SNPs previously genotyped in our GWAS of COME/ROM (N = 21) and those that failed Fluidigm assay design (N = 1), 26 SNPs were successfully genotyped in 716 individuals from our COME/ROM family population. None of the SNP associations replicated in our family-based population (unadjusted P = 0.03-0.93). Replication in an independent sample would confirm that these represent novel OM loci, and that further investigation is warranted.
| S-EPMC4121324 | biostudies-literature
Project description:The genetic factors leading to a predisposition to otitis media are not well understood. The objective of the current study was to develop a tag-single nucleotide polymorphism (SNP) panel to determine if there is an association between candidate gene polymorphisms and the development of chronic otitis media with effusion.A 1:1 case/control design of 100 cases and 100 controls was used. The study was limited to the chronic otitis media with effusion phenotype to increase the population homogeneity.A panel of 192 tag-SNPs was selected. Saliva for DNA extraction was collected from 100 chronic otitis media with effusion cases and 100 controls. After quality control, 100 case and 79 control samples were available for hybridization. Genomic DNA from each subject was hybridized to the SNP probes, and genotypes were generated. Quality control across all samples and SNPs reduced the final SNPs used for analysis to 170. Each SNP was then analyzed for statistical association with chronic otitis media with effusion.Eight SNPs from four genes had an unadjusted P value of <.05 for association with the chronic otitis media with effusion phenotype (TLR4, MUC5B, SMAD2, SMAD4); five of these polymorphisms were in the TLR4 gene.Even though these results need to be replicated in a novel population, the presence of five SNPs in the TLR4 gene having association with chronic otitis media with effusion in our study population lends evidence for the possible role of this gene in the susceptibility to otitis media.
| S-EPMC3971016 | biostudies-literature
Project description:BackgroundContemporary, quantitative data are needed to inform recommendations and decision-making regarding referral and surgeon endorsement of tympanostomy tube placement in young children with recurrent acute otitis media (AOM).MethodsA prospective, observational cohort study of 286 children in a primary care pediatric practice setting, who had at least 1 AOM (range 1-8). Children were followed longitudinally from 6 to 36 months old. AOMs were microbiologically confirmed by tympanocentesis for diagnostic accuracy. A window of susceptibility (WOS) was defined as AOMs closely spaced in time with no gap in occurrence >6 months. For prediction of total number of AOMs, we used a quasi-poisson generalized linear model.ResultsEighty percent of AOMs occurred during child age 6 to 21 months old. Seventy two percent of WOS intervals were <5 months and 97% were <10 months. Clinically applicable models were developed to predict which children would benefit most from tympanostomy tubes. Significant predictors were child age at the first AOM (P < .001) and daycare attendance (P = .03). The age of a child when 2, 3, or 4 AOMs had occurred allowed prediction of the number of additional AOMs that might occur. After insertion of tympanostomy tubes, 16 (52%) of 31 children had no additional AOMs.ConclusionsRecurrent AOM occurs in a narrow WOS and number of AOMs can be predicted at time of AOM based on child age and daycare attendance. Insertion of tympanostomy tubes likely occurs in many children after the WOS to recurrent AOM has passed or only 1 more AOM may be prevented at most.
| S-EPMC9890393 | biostudies-literature
Project description:BACKGROUND: Otitis media (OM) is a common childhood disease characterised by middle ear inflammation and effusion. Susceptibility to recurrent acute OM (rAOM; ? 3 episodes of AOM in 6 months) and chronic OM with effusion (COME; MEE ? 3 months) is 40-70% heritable. Few underlying genes have been identified to date, and no genome-wide association study (GWAS) of OM has been reported. METHODS AND FINDINGS: Data for 2,524,817 single nucleotide polymorphisms (SNPs; 535,544 quality-controlled SNPs genotyped by Illumina 660W-Quad; 1,989,273 by imputation) were analysed for association with OM in 416 cases and 1,075 controls from the Western Australian Pregnancy Cohort (Raine) Study. Logistic regression analyses under an additive model undertaken in GenABEL/ProbABEL adjusting for population substructure using principal components identified SNPs at CAPN14 (rs6755194: OR = 1.90; 95%CI 1.47-2.45; P(adj-PCA) = 8.3 × 10(-7)) on chromosome 2p23.1 as the top hit, with independent effects (rs1862981: OR = 1.60; 95%CI 1.29-1.99; P(adj-PCA) = 2.2 × 10(-5)) observed at the adjacent GALNT14 gene. In a gene-based analysis in VEGAS, BPIFA3 (P(Gene) = 2 × 10(-5)) and BPIFA1 (P(Gene) = 1.07 × 10(-4)) in the BPIFA gene cluster on chromosome 20q11.21 were the top hits. In all, 32 genomic regions show evidence of association (P(adj-PCA)<10(-5)) in this GWAS, with pathway analysis showing a connection between top candidates and the TGF? pathway. However, top and tag-SNP analysis for seven selected candidate genes in this pathway did not replicate in 645 families (793 affected individuals) from the Western Australian Family Study of Otitis Media (WAFSOM). Lack of replication may be explained by sample size, difference in OM disease severity between primary and replication cohorts or due to type I error in the primary GWAS. CONCLUSIONS: This first discovery GWAS for an OM phenotype has identified CAPN14 and GALNT14 on chromosome 2p23.1 and the BPIFA gene cluster on chromosome 20q11.21 as novel candidate genes which warrant further analysis in cohorts matched more precisely for clinical phenotypes.
| S-EPMC3485007 | biostudies-literature
Project description: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.
| S-EPMC8541908 | biostudies-literature