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

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tori C. Bootpetch ◽  
◽  
Lena Hafrén ◽  
Christina L. Elling ◽  
Erin E. Baschal ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Otitis Media ◽  
Middle Ear ◽  
Rare Variants ◽  
Common Disease ◽  
The Novel ◽  
Replication Studies ◽  
Genome Wide ◽  
Α Diversity ◽  
Rrna Sequencing

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.

Abstract 46: Whole Genome Sequence Analysis Of Blood Pressure Phenotypes In The Trans-omics For Precision Medicine And Centers For Common Disease Genomics Programs

Circulation ◽  
2020 ◽  
Vol 141 (Suppl_1) ◽  
Author(s):  
Tanika N Kelly ◽  
Xiao Sun ◽  
Jennifer A Brody ◽  
Sarah A Gagliano ◽  
Karen Y He ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Precision Medicine ◽  
Rare Variants ◽  
Minor Allele ◽  
Common Disease ◽  
Whole Genome ◽  
Genome Wide ◽  
Novel Variants ◽  
Discovery Stage ◽  
Genome Wide Significance

Background: Although genome-wide association studies (GWAS) have made important strides in localizing genomic regions associated with blood pressure (BP) phenotypes, the causal mechanisms underlying the vast majority of identified signals remain to be elucidated. Whole genome sequencing (WGS) provides an opportunity for novel genomic discoveries and high-resolution refinement of identified GWAS signals. Methods: This multi-stage genomic study of BP was conducted in an ancestrally diverse sample of up to 735,905 participants from 20 cohorts. In the discovery stage WGS study, variants with minor allele counts >10 were tested for association with systolic BP (SBP), diastolic BP (DBP), and hypertension (HTN) among 50,755 participants from the Trans-Omics for Precision Medicine and Centers for Common Disease Genomics programs using the Analysis Commons cloud based platform. Variants achieving suggestive genome-wide significance (P<1х10 -6 ) were tested for replication among UK Biobank (N=383,145) and Million Veterans Program (N=318,891) participants with GWAS data imputed to the TOPMed and 1000 Genomes reference panels, respectively. Results: Discovery stage analyses identified 63 novel loci suggestively associated with BP. As expected, most of these variants (81%) had minor allele frequencies (MAFs)<1%. Although none achieved genome-wide significance (P<5х10 -8 ) in joint analyses of discovery and replication stages, two rare variants had consistent effect directions and achieved nominal significance in replication analyses, including one for DBP at CHL1 (rs932205533; MAF=1.2х10 -4 ; joint β=18.0; joint P=7.4х10 -8 ) and one for SBP at MACROD2 (rs752530366; MAF=8.6х10 -4 ; joint β=-5.1; joint P=3.8х10 -6 ). A total of 44 novel variants from previously reported loci (r 2 <0.1 with previously reported variants) were also identified in the discovery stage analyses, including 31 rare variants with large effect sizes (70%). Nine common variants from these loci achieved genome-wide significance in joint analyses. Variants for SBP included ones at NPPB (rs12406089; MAF=0.34; joint β=-0.58; joint P=2.7х10 -79 ), AC137675.1 (rs2643826; MAF=0.56; joint β=0.56; joint P=1.5х10 -45 ), NEIL2 (rs804264; MAF=0.35; joint β=0.28; joint P=4.7х10 -20 ), CACNB2 (rs11014204; MAF=0.21; joint β=-0.53; joint P=6.8х10 -57 ), OVOL1 (rs557675; MAF=0.43; joint β=-0.25; joint P=1.9х10 -17 ), RP11-654D12.2 (rs8014582; MAF=0.05; joint β=-0.52; joint P=6.7х10 -13 ), and ATXN2 (rs35350651; MAF=0.67; joint β=-0.39; joint P=3.4х10 -38 ). Novel variants for DBP at INSR (rs36150639; MAF=0.45; joint β=-0.29; joint P=2.5х10 -27 ) and HTN at TBX3 (rs2891546; MAF=0.17; joint OR=0.95; joint P=3.1х10 -14 ) were also identified. Conclusion: WGS studies in large multi-ancestry samples can identify novel signals at previously reported GWAS loci, helping to localize causal genes and variants for BP.

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

2020 ◽  
pp. jmedgenet-2020-106844 ◽  
Author(s):  
Daniel N. Frank ◽  
Arnaud P. J. Giese ◽  
Lena Hafren ◽  
Tori C. Bootpetch ◽  
Talitha Karisse L. Yarza ◽  
...  
Keyword(s):  
Oral Cavity ◽  
Head And Neck ◽  
Otitis Media ◽  
Middle Ear ◽  
Rare Variants ◽  
Missense Variant ◽  
Middle Ear Mucosa ◽  
Significant Heritability ◽  
Epithelial Barriers ◽  
And Shifts

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.

scholarly journals Shortwave infrared otoscopy for diagnosis of middle ear effusions: a machine-learning-based approach

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rustin G. Kashani ◽  
Marcel C. Młyńczak ◽  
David Zarabanda ◽  
Paola Solis-Pazmino ◽  
David M. Huland ◽  
...  
Keyword(s):  
Machine Learning ◽  
Otitis Media ◽  
Middle Ear ◽  
Infrared Region ◽  
Common Disease ◽  
Specificity And Sensitivity ◽  
Traditional Approaches ◽  
Shortwave Infrared ◽  
Made In

AbstractOtitis media, a common disease marked by the presence of fluid within the middle ear space, imparts a significant global health and economic burden. Identifying an effusion through the tympanic membrane is critical to diagnostic success but remains challenging due to the inherent limitations of visible light otoscopy and user interpretation. Here we describe a powerful diagnostic approach to otitis media utilizing advancements in otoscopy and machine learning. We developed an otoscope that visualizes middle ear structures and fluid in the shortwave infrared region, holding several advantages over traditional approaches. Images were captured in vivo and then processed by a novel machine learning based algorithm. The model predicts the presence of effusions with greater accuracy than current techniques, offering specificity and sensitivity over 90%. This platform has the potential to reduce costs and resources associated with otitis media, especially as improvements are made in shortwave imaging and machine learning.

Hand Demonstration of the Anatomy and Function of the Eustachian Tube

1995 ◽  
Vol 112 (5) ◽  
pp. P58-P58
Author(s):  
Isamu Sando
Keyword(s):  
Otitis Media ◽  
Eustachian Tube ◽  
Middle Ear ◽  
Common Cold ◽  
Otitis Media With Effusion ◽  
Three Dimensional ◽  
Common Disease ◽  
Educational Objectives ◽  
The Common ◽  
And Function

Educational objectives: To understand three-dimensional anatomy and function of the eustachian tube and consequently the pathology and dysfunction of the eustachian tube that are closely associated with those of the middle ear, such as otitis media with effusion, the second most common disease among children, next to the common cold.

scholarly journals Evolution, revolution and heresy in the genetics of infectious disease susceptibility

2012 ◽  
Vol 367 (1590) ◽  
pp. 840-849 ◽  
Author(s):  
Adrian V. S. Hill
Keyword(s):  
Infectious Disease ◽  
Infectious Diseases ◽  
Large Scale ◽  
Disease Susceptibility ◽  
Rare Variants ◽  
Association Studies ◽  
Common Disease ◽  
Genome Wide Association Studies ◽  
Case Control Studies ◽  
Genome Wide

Infectious pathogens have long been recognized as potentially powerful agents impacting on the evolution of human genetic diversity. Analysis of large-scale case–control studies provides one of the most direct means of identifying human genetic variants that currently impact on susceptibility to particular infectious diseases. For over 50 years candidate gene studies have been used to identify loci for many major causes of human infectious mortality, including malaria, tuberculosis, human immunodeficiency virus/acquired immunodeficiency syndrome, bacterial pneumonia and hepatitis. But with the advent of genome-wide approaches, many new loci have been identified in diverse populations. Genome-wide linkage studies identified a few loci, but genome-wide association studies are proving more successful, and both exome and whole-genome sequencing now offer a revolutionary increase in power. Opinions differ on the extent to which the genetic component to common disease susceptibility is encoded by multiple high frequency or rare variants, and the heretical view that most infectious diseases might even be monogenic has been advocated recently. Review of findings to date suggests that the genetic architecture of infectious disease susceptibility may be importantly different from that of non-infectious diseases, and it is suggested that natural selection may be the driving force underlying this difference.

Acute otitis media increases middle ear susceptibility to nasal injection of

1994 ◽  
Vol 110 (1) ◽  
pp. 115-121 ◽  
Author(s):  
P ANTONELLI ◽  
S JUHN ◽  
C LE ◽  
G GIEBINK
Keyword(s):  
Otitis Media ◽  
Middle Ear ◽  
Acute Otitis Media

Middle ear tuberculosis - clinical case

ORL ro ◽  
2016 ◽  
Vol 2 (1) ◽  
pp. 12-14
Author(s):  
A. Sandul ◽  
M. Buracovschi ◽  
N. Buracovschi
Keyword(s):  
Otitis Media ◽  
Middle Ear ◽  
Human Population ◽  
Clinical Case ◽  
Correct Diagnosis ◽  
Tuberculous Otitis Media ◽  
Type V

Tuberculosis is one of the oldest pathologies that affect human population, being a significant cause of morbidity/mortality in several countries. Middleear tuberculosis is a rare pathology, often misdiagnosed because of an atipic evolution, as a result leading to severe complications. This paper presents a case of tuberculous otitis media complicated with facial nerveparalysis House Brackmann type V in a patient who underwent multiple middleear surgeries before correct diagnosis was established.  

Comparison of the Aditus ad Antrum Diameter on CT between Patients with Chronic Otitis Media and Healthy Individuals

2019 ◽  
Vol 15 (10) ◽  
pp. 990-993 ◽  
Author(s):  
Elif Gündoğdu ◽  
Uğur Toprak
Keyword(s):  
Computed Tomography ◽  
Otitis Media ◽  
Middle Ear ◽  
Healthy Subjects ◽  
Normal Values ◽  
Chronic Otitis Media ◽  
Healthy Individuals ◽  
Inner Diameter ◽  
Male Patients ◽  
The Right

Background: The middle ear cavity is ventilated through the aditus ad antrum. Aditus blockage contributes to the pathology of otitis media. Objective: To determine the normal values of the aditus ad antrum diameter on computed tomography and to investigate its relationship with chronic otitis media and related pathologies (tympanosclerosis and myringosclerosis). Methods: The temporal CT images of 162 individuals were evaluated retrospectively. In the axial sections, the inner diameter of the aditus was measured at the narrowest point at the cortex. The differences in diameter were compared between diseased and healthy ears. Results: In healthy individuals, the diameter was narrower in women. There was no difference between the right and left ears in healthy subjects. No correlation was found between age and diameter. In male patients with myringosclerosis, the diameter was slightly narrower on both sides but more marked on the left. In female patients with myringosclerosis, the diameter in both ears was slightly narrower. In cases of otitis media and tympanosclerosis, the diameter was less than that of healthy individuals, despite the lack of statistically significant result in all cases. Conclusion: The aditus ad antrum was narrower in diseased ears, indicating that a blocked aditus may contribute to the development of otitis media, as well as mucosal diseases.

scholarly journals Common and rare genetic variants that could contribute to severe otitis media in an Australian Aboriginal population

2021 ◽  
Author(s):  
Sarra E Jamieson ◽  
Michaela Fakiola ◽  
Dave Tang ◽  
Elizabeth Scaman ◽  
Genevieve Syn ◽  
...  
Keyword(s):  
Hair Cell ◽  
Otitis Media ◽  
Genetic Risk ◽  
Transforming Growth Factor ◽  
Rare Variants ◽  
Protein Coding ◽  
Gene Sets ◽  
Growth Factor Signalling ◽  
Rare Genetic Variants ◽  
And Function

Abstract 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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