Pharmacological Approaches to Hearing Loss

Pharmacological Reviews, Journal Year: 2024, Volume and Issue: 76(6), P. 1063 - 1088

Published: Oct. 16, 2024

Hearing disorders pose significant challenges to individuals experiencing them and their overall quality of life, emphasizing the critical need for advanced pharmacological approaches address these conditions. Current treatment options often focus on amplification devices, cochlear implants, or other rehabilitative therapies, leaving a substantial gap regarding effective interventions. Advancements in our understanding molecular cellular mechanisms involved hearing induced by noise, aging, ototoxicity have opened new avenues drug development, some which led numerous clinical trials, with promising results. The development optimal delivery solutions animals humans can also enhance targeted medications ear. Moreover, large genome studies contributing genetic loss combined technologies animal shown great potential increase etiologies loss. auditory system exhibits circadian rhythms temporal variations its physiology, vulnerability insults, responsiveness treatments. clock are under control glucocorticoid system, preclinical evidence suggests that risk/benefit profile disorder treatments using chronopharmacological would be beneficial. If translatable bedside, such may improve outcome trials. Ongoing research into basis disorders, coupled advancements formulation as well optimized timing administration, holds promise more SIGNIFICANCE STATEMENT: procedures

Language: Английский

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Large-scale audiometric phenotyping identifies distinct genes and pathways involved in hearing loss subtypes

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

Summary Age-related hearing loss affects one-third of the population over 65 years. However, diverse pathologies underlying these heterogenous phenotypes complicate genetic studies. To overcome challenges associated with accurate phenotyping for older adults loss, we applied computational approaches based on audiometrically measured loss. This novel strategy uncovered distinct variants sensory and metabolic Sex-stratified analyses sexually dimorphic revealed a locus relevance to in males, but not females. Enrichment that genes involved frontotemporal dementia were implicated while relating processing sound by hair cells Our study has enhanced our understanding two phenotypes, representing first step development more precise treatments pathologically phenotypes.

Language: Английский

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IMPC impact on preclinical mouse models

Mammalian Genome, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 16, 2025

21 academic research institutions across 15 countries on 5 continents, including leading laboratories from Europe, North America, Asia, and Africa.IMPC members agreed a mission to "create comprehensive catalog of mammalian gene function that is freely available for researchers" by producing mouse models with targeted disruptions every human orthologous protein-coding in the genome.These knockout have been continue be subjected standardized series phenotyping assays multiple body systems (Brown Moore 2012a, b;Brown et al. 2005), allowing identification key biological processes functional pleiotropy Lad 2019), sexual dimorphism (Karp 2017;Wilson 2022), essentiality each (Cacheiro 2020).Depositing mice data into publicly accessible repositories are making these resources researchers around world extend this new knowledge studies genetic effects specific disease mechanisms.These efforts aim accelerate diagnoses, identify druggable targets, develop novel therapeutic interventions, enact effective prevention strategies (Groza 2023). The impactTo date, emerging study IMPC has become an invaluable scientific resource biomedical community, facilitating targets diseases.The vast phenotypic generated not only project consortium itself but also greater community using IMPC-generated substantially enhanced our understanding gene-disease relationships influences mechanisms disease.A publication tracking system natural language processing methods, followed annotator reviews through IMPC-specific literature monitoring curation tool 2024), identified nearly 7,500 papers used mice, data, and/or biomaterials challengeComplete sequencing genomes human, mouse, several other species was technological breakthrough mapped thousands genes non-coding regions, much which had heretofore unknown.But it soon became apparent significant gaps existed vivo most genes.Scientific progress address deficiency painstakingly slow arduous, resulting partial annotation small number well-characterized sets.This self-fulfilling paradigm overlooked little no known function, leaving its wake neglected "dark" genome.To reveal insights associations causes disease, fundamental shift incremental steps transformative change needed.In response, collaborative, global initiative emerged systematically generate phenotype collection genetically modified "knockout" models.

Language: Английский

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Sleep-Associated Traits and Hearing Difficulties in Noise: A Bidirectional Mendelian Randomization Study

Ear and Hearing, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 20, 2025

Objectives: The aim of this study was to investigate the causal relationships between sleep-associated traits and hearing difficulties in noise (HDinN) by Mendelian randomization (MR) analysis. Design: Single nucleotide polymorphisms associated with chronotype, insomnia, sleep duration, daytime dozing or sleeping, ease getting up morning were extracted from European population genome-wide association pooled data for bidirectional MR MR-Egger regression, inverse variance weighted technique, median method used then expanded include South Asian, East African, Greater Middle Eastern populations. Results: analysis indicated that populations, is a protective factor HDinN (odds ratio [OR] = 0.932, p 4.22 × 10 −5 , FDR 5.62 −4 ), while shorter duration risk (undersleepers: OR 1.164, 0.002, 0.014). In addition, there an indicative (OR 1.089, 0.046, 0.123). conclusions consistent African populations (ease up: 0.696, 0.012, 0.041, duration: 0.677, 0.032 0.091, dozing: reverse direction, significant both chronotype 1.413, 0.011, 0.042) 0.668, 1.75 3.49 ) similar respectively reached Asian 1.085, 0.010, 0.045) 0.936, 0.012). Furthermore, although not observed exploratory studies non-European suggested potential insomnia (East Asian: 1.920, 0.043, African: 2.080, 0.004, 0.019, 1.981, 1.59 P Eastern: 2.394, 0.012), vice versa (Greater 1.056, 0.014, 0.044). Conclusions: This identified relationship HDinN. However, underlying mechanisms reported here have yet be elucidated.

Language: Английский

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Mendelian non-syndromic and syndromic hearing loss genes contribute to presbycusis

European Journal of Human Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: March 7, 2025

Age-related (AR) hearing loss (HL) is the most prevalent sensorineural disorder in older adults. Here we demonstrate that rare-variants well-established Mendelian HL genes play an important role ARHL etiology. In all identified 32 which are associated with ARHL. We performed single and rare-variant aggregate association analyses using exome data obtained from white-Europeans self-reported phenotypes UK Biobank. Our analysis revealed previously unreported associations between non-syndromic syndromic genes, including MYO15A, WFS1. Additionally, i.e., ACTG1, GRHL2, KCNQ4, MYO7A, PLS1, TMPRSS3, TNRC6B. Four novel were also detected: FBXO2 PALM3, implicated mice, TWF1, Dalmatian dogs, TXNDC17. In-silico provided further evidence of inner ear expression these both murine human models, supporting their relevance to Analysis variants minor allele frequency >0.005 additional known e.g., ILDR1 ABHD12, COA8, KANSL1, SERAC1, UBE3B as well have not been reported be involved VCL. Rare-variants typically exhibited higher effect sizes for compared those other genes. conclusion, this study highlights critical etiology

Language: Английский

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Variant Reclassification in Underrepresented Minority Children With Sensorineural Hearing Loss

Ear and Hearing, Journal Year: 2025, Volume and Issue: unknown

Published: March 12, 2025

Objectives: Underrepresented minority (URM, comprising Hispanic, non-Hispanic Black, and Native American) children with sensorineural hearing loss have fivefold lower odds of receiving a genetic diagnosis after undergoing gene-panel testing. Using loss-specific American College Medical Genetics (ACMG)/Association for Molecular Pathology (AMP) guidelines applied to URM-specific cohort demonstrates the utility these in reducing disparity diagnostic efficacy testing URM populations. Design: A total 2740 variants from 715 patients (1275 348 patients) were queried. ACMG variant interpretation expert specification used attempt reclassification multihit (≥2 occurrences) uncertain significances (VUSs), focusing on case-control analysis relative ancestry-matched controls computational prediction. Results: Before curation, only 198 1275 (15.52%) population classified as likely pathogenic. Sixty-one VUSs, including OTOG , TJP2 COL11A2 34 other genes, probed using ACMG/AMP guidelines, resulting 19 variants. For remaining 42 would require parental segregation analysis. In addition VUSs that appeared at least twice our dataset, many additional once, but extremely rare or absent databases could be reclassified information. Conclusions: This study application HL-specific classification specifically dramatic effects it can clarifying pathogenicity thus contributing clinicians’ ability improve standard care improved accuracy subsequent early intervention.

Language: Английский

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A Systematic Review on the Genetic Contribution to Tinnitus

Journal of the Association for Research in Otolaryngology, Journal Year: 2024, Volume and Issue: 25(1), P. 13 - 33

Published: Feb. 9, 2024

Abstract Purpose To assess the available evidence to support a genetic contribution and define role of common rare variants in tinnitus. Methods After systematic search quality assessment, 31 records including 383,063 patients were selected (14 epidemiological studies 17 association studies). General information on sample size, age, sex, tinnitus prevalence, severe distribution, sensorineural hearing loss was retrieved. Studies that did not include data assessment excluded. Relative frequencies used for qualitative variables compare different obtain average values. Genetic genes listed clustered according their potential development. Results The prevalence estimated from population-based 26.3% any tinnitus, 20% with reported it as an annoying symptom. One study has population-specific differences white ancestry being population higher prevalence. Genome-wide have identified replicated two Chinese (rs2846071; rs4149577) intron TNFRSF1A , associated noise-induced Moreover, gene burden analyses sequencing Spanish Swede ANK2 AKAP9 TSC2 genes. Conclusions is starting be revealed shows effects European Asian populations. allelic showed replication are Although been large effect, or hyperacusis established.

Language: Английский

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Polygenic Risk Score Modifies the Association of HbA1c With Hearing Loss in Middle-Aged and Older Chinese: The Dongfeng-Tongji Cohort

Diabetes Care, Journal Year: 2024, Volume and Issue: 47(7), P. 1186 - 1193

Published: May 10, 2024

Evidence regarding the modifying effect of polygenic risk score (PRS) on associations between glycemic traits and hearing loss (HL) was lacking. We aimed to examine whether these can be influenced by genetic susceptibility.

Language: Английский

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Sex differences in the polygenic architecture of hearing problems in adults

Genome Medicine, Journal Year: 2023, Volume and Issue: 15(1)

Published: May 10, 2023

Hearing problems (HP) in adults are common and associated with several comorbid conditions. Its prevalence increases age, reflecting the cumulative effect of environmental factors genetic predisposition. Although risk loci have been already identified, HP biology epidemiology still insufficiently investigated by large-scale studies.

Language: Английский

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Investigating the characteristics of genes and variants associated with self-reported hearing difficulty in older adults in the UK Biobank

BMC Biology, Journal Year: 2022, Volume and Issue: 20(1)

Published: June 27, 2022

Abstract Background Age-related hearing loss is a common, heterogeneous disease with strong genetic component. More than 100 loci have been reported to be involved in human impairment date, but most of the genes underlying adult-onset remain unknown. Most studies focussed on very rare variants (such as family and patient cohort screens) or common (genome-wide association studies). However, contribution present population at intermediate frequencies hard quantify using these methods, result, landscape variation associated remains largely Results Here we study based exome sequencing self-reported difficulty UK Biobank, large-scale biomedical database. We carried out variant load analyses different minor allele frequency impact filters, compared resulting gene lists manually curated list nearly 700 known humans and/or mice. An cutoff 0.1, combined high predicted impact, was found effective filter setting for our analysis. also that separating participants by sex produced markedly lists. The obtained were investigated ontology annotation, functional prioritisation expression analysis, this identified good candidates further study. Conclusions Our results suggest relatively well contribute age-related contributions adult may differ between sexes. deafness useful resource candidate loss.

Language: Английский

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