Exploring causal correlations between inflammatory cytokines and Ménière's disease: a Mendelian randomization.

Objectives: Previous studies have highlighted associations between certain inflammatory cytokines and Ménière's Disease (MD), such as interleukin (IL) -13 and IL-1ß. This Mendelian randomization aims to comprehensively evaluate the causal relationships between 91 inflammatory cytokines and MD. Methods: A comprehensive two-sample Mendelian randomization (MR) analysis was conducted to determine the causal association between inflammatory cytokines and MD. Utilizing publicly accessible genetic datasets, we explored causal links between 91 inflammatory cytokines and MD risk. Comprehensive sensitivity analyses were employed to assess the robustness, heterogeneity, and presence of horizontal pleiotropy in our findings. Results: Our findings indicate that MD causally influences the levels of two cytokine types: IL-10 (P=0.048, OR=0.945, 95%CI =0.894~1.000) and Neurotrophin-3 (P=0.045, OR=0954, 95%CI =0.910~0.999). Furthermore, three cytokines exhibited significant causal effects on MD: CD40L receptor (P=0.008, OR=0.865, 95%CI =0.777-0.963), Delta and Notch-like epidermal growth factor-related receptor (DNER) (P=0.010, OR=1.216, 95%CI =1.048-1.412), and STAM binding protein (P=0.044, OR=0.776, 95%CI =0.606-0.993). Conclusion: This study suggests that the CD40L receptor, DNER, and STAM binding protein could potentially serve as upstream determinants of MD. Furthermore, our results imply that when MD is regarded as the exposure variable in MR analysis, it may causally correlate with elevated levels of IL-10 and Neurotrophin-3. Using these cytokines for MD diagnosis or as potential therapeutic targets holds great clinical significance.

An overload of missense variants in the OTOG gene may drive a higher prevalence of familial Meniere disease in the European population.

Meniere disease is a complex inner ear disorder with significant familial aggregation. A differential prevalence of familial MD (FMD) has been reported, being 9-10% in Europeans compared to 6% in East Asians. A broad genetic heterogeneity in FMD has been described, OTOG being the most common mutated gene, with a compound heterozygous recessive inheritance. We hypothesize that an OTOG-related founder effect may explain the higher prevalence of FMD in the European population. Therefore, the present study aimed to compare the allele frequency (AF) and distribution of OTOG rare variants across different populations. For this purpose, the coding regions with high constraint (low density of rare variants) were retrieved in the OTOG coding sequence in Non-Finnish European (NFE).. Missense variants (AF < 0.01) were selected from a 100 FMD patient cohort, and their population AF was annotated using gnomAD v2.1. A linkage analysis was performed, and odds ratios were calculated to compare AF between NFE and other populations. Thirteen rare missense variants were observed in 13 FMD patients, with 2 variants (rs61978648 and rs61736002) shared by 5 individuals and another variant (rs117315845) shared by two individuals. The results confirm the observed enrichment of OTOG rare missense variants in FMD. Furthermore, eight variants were enriched in the NFE population, and six of them were in constrained regions. Structural modeling predicts five missense variants that could alter the otogelin stability. We conclude that several variants reported in FMD are in constraint regions, and they may have a founder effect and explain the burden of FMD in the European population.

Causality between alcohol usually taken with meals and Meniere disease: A 2-sample Mendelian randomization study.

The recurrence of Meniere disease (MD) strongly affects patient quality of life. Identifying the risk factors for MD is highly important for its prevention and treatment. Previous studies have suggested that alcohol intake may play a role in the development of MD. However, recent studies have shown that the causal relationship between alcohol consumption and MD remains controversial. In this paper, the Mendelian randomization (MR) method was used to determine the causal relationship between alcohol consumption usually consumed with meals and MD, with the aim of providing suggestions for alcohol intake management in individuals with MD and helping in the prevention and treatment of MD. Two-sample MR was used to investigate the causal relationship between alcohol usually taken with meals and MD. We used a dataset from a publicly available large-scale genome-wide association study (GWAS). Inverse variance weighting (IVW), MR-Egger, simple weighting, weighted weighting and the weighted median method were used for analysis. The final results showed that IVW (OR = 0.991, 95% CI: 0.983-0.998, P = .016) results suggested that there was statistical significance, but MR-Egger (OR = 0.978, 95% CI: 0.886-1.080, P = .679), weighted median methods (OR = 0.994, 95% CI: 0.985-1.004, P = .307) and Simple mode (OR = 0.995, 95% CI: 0.980-1.010, P = .566), Weighted mode (OR = 0.995, 95% CI: 0.981-1.010, P = .557) found no significant causal relationship. The results suggest that alcohol usually taken with meals may be negatively correlated with MD.

Epidemiology and genetics of Meniere's disease.

PURPOSE OF REVIEW: This review discusses the recent developments on the understanding of epidemiology and genetics of Meniere's disease. RECENT FINDINGS: Meniere's disease has been shown to be associated with several comorbidities, such as migraine, anxiety, allergy and immune disorders. Recent studies have investigated the relationship between environmental factors and Meniere's disease such as air pollution, allergy, asthma, osteoporosis or atmospheric pressure, reporting specific comorbidities in East Asian population. The application of exome sequencing has enabled the identification of genes sharing rare missense variants in multiple families with Meniere's disease, including OTOG and TECTA and suggesting digenic inheritance in MYO7A . Moreover, knockdown of DTNA gene orthologue in Drosophila resulted in defective proprioception and auditory function. DTNA and FAM136A knockout mice have been studied as potential mouse models for Meniere's disease. SUMMARY: While it has attracted emerging attention in recent years, the study of Meniere's disease genetics is still at its early stage. More geographically and ethnically based human genome studies, and the development of cellular and animal models of Meniere's disease may help shed light on the molecular mechanisms of Meniere's disease and provide the potential for gene-specific therapies.

Psychological Distress and Meniere's Disease: A Bidirectional Two-Sample Mendelian Randomization Study.

OBJECTIVE: This study is aim to explore the causal relationship between anxiety, depression, neuroticism, and Meniere's disease (MD). STUDY DESIGN: Two-sample bidirectional Mendelian randomization (MR) analyses. SETTING: IEU, FinnGen, CTG, and UKB databases. METHODS: The genome-wide association studies data for anxiety, depression, neuroticism, and MD involved over 357,957 participants. MR was performed to explore relationships between anxiety, depression, neuroticism, and MD. Sensitivity analyses were performed to assess the robustness of the MR results. Reverse MR was used to exclude the possibility of reverse causality. Finally, multivariate MR was performed to explore the collinear relationships between neuroticism subclusters. RESULTS: MR results showed that anxiety and depression are not causes of MD, nor does MD cause anxiety and depression. Elevated neuroticism sum score is a cause of anxiety, depression, and MD, but MD does not lead to an increase in the level of neuroticism sum score. Further analysis showed that the 5 subclusters of neuroticism often feel lonely, mood often goes up and down, often feel fed-up, feelings easily hurt, and sensitivity to environmental stress and adversity are causes of MD. Multivariate MR analysis results suggested that the 5 neuroticism subclusters have a collinear relationship. CONCLUSION: Anxiety and depression are not causative factors of MD, and vice versa. Elevated neuroticism levels serve as a shared causative factor for anxiety, depression, and MD. Identification and effective management of neuroticism is a potential target for preventing and treating MD.

RotaRod and acoustic startle reflex performance of two potential mouse models for Meniere's disease.

Meniere's disease (MD) is a disorder of the inner ear characterized by chronic episodes of vertigo, tinnitus, increased aural pressure, and sensorineural hearing loss. Causes of MD are unknown, but endolymphatic hydrops is a hallmark. In addition, 5%-15% of MD cases have been identified as familial. Whole-genome sequencing studies of individuals with familial MD identified DTNA and FAM136A as candidate genes for autosomal dominant inheritance of MD. Although the exact roles of these genes in MD are unknown, FAM136A encodes a mitochondrial protein, and DTNA encodes a cytoskeletal protein involved in synapse formation and maintenance, important for maintaining the blood-brain barrier. It is also associated with a particular aquaporin. We tested vestibular and auditory function in dtna and fam136a knockout (KO) mice, using RotaRod and startle reflex-based clicker tests, respectively. Three-factor analysis of variance (ANOVA) results indicated that sex, age, and genotype were significantly correlated with reduced mean latencies to fall ("latencies") for male dtna KO mice, while only age was a significant factor for fam136a KO mice. Fam136a KO mice lost their hearing months before WTs (9-11 months vs. 15-20 months). In male dtna KO mice, divergence in mean latencies compared with other genotypes was first evident at 4 months of age, with older males having an even greater decrease. Our results indicate that fam136a gene mutations generate hearing problems, while dtna gene mutations produce balance deficits. Both mouse models should help to elucidate hearing loss and balance-related symptoms associated with MD.

Application of Human Stem Cells to Model Genetic Sensorineural Hearing Loss and Meniere Disease.

Genetic sensorineural hearing loss and Meniere disease have been associated with rare variations in the coding and non-coding region of the human genome. Most of these variants were classified as likely pathogenic or variants of unknown significance and require functional validation in cellular or animal models. Given the difficulties to obtain human samples and the raising concerns about animal experimentation, human-induced pluripotent stem cells emerged as cellular models to investigate the interaction of genetic and environmental factors in the pathogenesis of inner ear disorders. The generation of human sensory epithelia and neuron-like cells carrying the variants of interest may facilitate a better understanding of their role during differentiation. These cellular models will allow us to explore new strategies for restoring hearing and vestibular sensory epithelia as well as neurons. This review summarized the use of human-induced pluripotent stem cells in sensorineural hearing loss and Meniere disease and proposed some strategies for its application in clinical practice.

Types of Inheritance and Genes Associated with Familial Meniere Disease.

Meniere disease (MD) is a rare disorder of the inner ear defined by sensorineural hearing loss (SNHL) associated with episodes of vertigo and tinnitus. The phenotype is variable, and it may be associated with other comorbidities such as migraine, respiratory allergies, and several autoimmune disorders. The condition has a significant heritability according to epidemiological and familial segregation studies. Familial MD is found in 10% of cases, the most frequently found genes being OTOG, MYO7A, and TECTA, previously associated with autosomal dominant and recessive non-syndromic SNHL. These findings suggest a new hypothesis where proteins involved in the extracellular structures in the apical surface of sensory epithelia (otolithic and tectorial membranes) and proteins in the stereocilia links would be key elements in the pathophysiology of MD. The ionic homeostasis of the otolithic and tectorial membranes could be critical to suppress the innate motility of individual hair cell bundles. Initially, focal detachment of these extracellular membranes may cause random depolarization of hair cells and will explain changes in tinnitus loudness or trigger vertigo attacks in early stages of MD. With the progression of the disease, a larger detachment will lead to an otolithic membrane herniation into the horizontal semicircular canal with dissociation in caloric and head impulse responses. Familial MD shows different types of inheritance, including autosomal dominant and compound recessive patterns and implementation of genetic testing will improve our understanding of the genetic structure of MD.

Genetic advances in Meniere Disease.

Meniere Disease (MD) is an idiopathic inner ear disease with complex etiology and pathogenesis, which is still unclear. With the development in gene analysis technology, the genetic research of MD has attracted extensive attention, resulting in a large number of studies on the research of the relationship between human genes and MD. This paper aims to review the studies on this topic in recent years. The studies mainly focused on the genetics of familial MD and the correlation between MD and potentially related functional genes. The results of these studies have demonstrated the complexity and diversity of the pathogenesis of MD with both genetic and epigenetic alterations, suggesting that MD might be related to inflammation, immunity, aqua and ion balance in the lymphatic fluid, virus infection, metabolism, and abnormal function of nerve conduction. The finding of rare mutations in TECTA, MYO7A and OTOG genes and other genes such as CDH23, PCDH15 and ADGRV1 in the same families suggest that the integrity of the stereocilia and their interaction with the tectorial and otolithic membranes could be involved in the pathophysiology of familial MD.

Rare Deletions or Large Duplications Contribute to Genetic Variation in Patients with Severe Tinnitus and Meniere Disease.

Meniere disease (MD) is a debilitating disorder of the inner ear defined by sensorineural hearing loss (SNHL) associated with episodes of vertigo and tinnitus. Severe tinnitus, which occurs in around 1% of patients, is a multiallelic disorder associated with a burden of rare missense single nucleotide variants in synaptic genes. Rare structural variants (SVs) may also contribute to MD and severe tinnitus. In this study, we analyzed exome sequencing data from 310 MD Spanish patients and selected 75 patients with severe tinnitus based on a Tinnitus Handicap Inventory (THI) score > 68. Three rare deletions were identified in two unrelated individuals overlapping the ERBB3 gene in the positions: NC_000012.12:g.56100028_56100172del, NC_000012.12:g.56100243_56101058del, and NC_000012.12:g.56101359_56101526del. Moreover, an ultra-rare large duplication was found covering the AP4M1, COPS6, MCM7, TAF6, MIR106B, MIR25, and MIR93 genes in another two patients in the NC_000007.14:g.100089053_100112257dup region. All the coding genes exhibited expression in brain and inner ear tissues. These results confirm the contribution of large SVs to severe tinnitus in MD and pinpoint new candidate genes to get a better molecular understanding of the disease.

Repurposable Drugs That Interact with Steroid Responsive Gene Targets for Inner Ear Disease.

Corticosteroids, oral or transtympanic, remain the mainstay for inner ear diseases characterized by hearing fluctuation or sudden changes in hearing, including sudden sensorineural hearing loss (SSNHL), Meniere's disease (MD), and autoimmune inner ear disease (AIED). Despite their use across these diseases, the rate of complete recovery remains low, and results across the literature demonstrates significant heterogeneity with respect to the effect of corticosteroids, suggesting a need to identify more efficacious treatment options. Previously, our group has cross-referenced steroid-responsive genes in the cochlea with published single-cell and single-nucleus transcriptome datasets to demonstrate that steroid-responsive differentially regulated genes are expressed in spiral ganglion neurons (SGN) and stria vascularis (SV) cell types. These differentially regulated genes represent potential druggable gene targets. We utilized multiple gene target databases (DrugBank, Pharos, and LINCS) to identify orally administered, FDA approved medications that potentially target these genes. We identified 42 candidate drugs that have been shown to interact with these genes, with an emphasis on safety profile, and tolerability. This study utilizes multiple databases to identify drugs that can target a number of druggable genes in otologic disorders that are commonly treated with steroids, providing a basis for establishing novel repurposing treatment trials.

New Genetic Variants in CYP2B6 and SLC6A Support the Role of Oxidative Stress in Familial Ménière's Disease.

The objective was to study the genetic etiology of Ménière's disease (MD) using next-generation sequencing in three families with three cases of MD. Whole exome sequencing was used to identify rare genetic variants co-segregating with MD in Finnish families. In silico estimations and population databases were used to estimate the frequency and pathogenicity of the variants. Variants were validated and genotyped from additional family members using capillary sequencing. A geneMANIA analysis was conducted to investigate the functional pathways and protein interactions of candidate genes. Seven rare variants were identified to co-segregate with MD in the three families: one variant in the CYP2B6 gene in family I, one variant in GUSB and EPB42 in family II, and one variant in each of the SLC6A, ASPM, KNTC1, and OVCH1 genes in family III. Four of these genes were linked to the same co-expression network with previous familial MD candidate genes. Dysfunction of CYP2B6 and SLC6A could predispose to MD via the oxidative stress pathway. Identification of ASPM and KNTC1 as candidate genes for MD suggests dysregulation of mitotic spindle formation in familial MD. The genetic etiology of familial MD is heterogenic. Our findings suggest a role for genes acting on oxidative stress and mitotic spindle formation in MD but also highlight the genetic complexity of MD.

Association of Pro-inflammatory Cytokine Gene Polymorphism with Meniere's Disease in an Iranian Sample.

Meniere's disease (MD) is known as a rare chronic disorder of the inner ear with elevated serum levels of pro-inflammatory cytokines like tumor necrosis factor (TNF)-α, Interleukin (IL)-1, and IL-6. This study aims to evaluate genes polymorphism in some pro-inflammatory cytokines in a group of Iranian MD patients compared to the healthy controls. In this case-control study, 25 MD patients and 139 healthy controls were enrolled. DNA was extracted from blood samples, and single nucleotide polymorphisms were detected using polymerase chain reaction with sequence-specific primers assay. MD patients and controls were examined in terms of allele, genotype, and haplotype frequency of pro-inflammatory cytokine genes. Only the frequencies of alleles A/G at position -238 in the promoter of the TNF-α gene differed significantly between MD patients and healthy controls. G to A allele ratio was 23 and 3.6 in MD and controls, respectively. In individuals with MD, genotype GG was found to be significantly more prevalent at position -238 of the TNF-α gene promoter sequence. In addition, the heterozygote AG variant of -238 A/G TNF-α gene polymorphism was lower in MD patients than controls. Compared to the control group, the haplotype TNF- (-308, -238) AG was higher in MD patients, although not statistically significant. This is the first study that we know of that evaluates the frequencies of pro-inflammatory cytokine genes in an Iranian MD sample. This study shows the association between TNF-α and susceptibility to MD.

Rare coding variants involving MYO7A and other genes encoding stereocilia link proteins in familial meniere disease.

The MYO7A gene encodes a motor protein with a key role in the organization of stereocilia in auditory and vestibular hair cells. Rare variants in the MYO7A (myosin VIIA) gene may cause autosomal dominant (AD) or autosomal recessive (AR) sensorineural hearing loss (SNHL) accompanied by vestibular dysfunction or retinitis pigmentosa (Usher syndrome type 1B). Familial Meniere's disease (MD) is a rare inner ear syndrome mainly characterized by low-frequency sensorineural hearing loss and episodic vertigo associated with tinnitus. Familial aggregation has been found in 6-8% of sporadic cases, and most of the reported genes were involved in single families. Thus, this study aimed to search for relevant genes not previously linked to familial MD. Through exome sequencing and segregation analysis in 62 MD families, we have found a total of 1 novel and 8 rare heterozygous variants in the MYO7A gene in 9 non-related families. Carriers of rare variants in MYO7A showed autosomal dominant or autosomal recessive SNHL in familial MD. Additionally, some novel and rare variants in other genes involved in the organization of the stereocilia links such as CDH23, PCDH15 or ADGRV1 co-segregated in the same patients. Our findings reveal a co-segregation of rare variants in the MYO7A gene and other structural myosin VIIA binding proteins involved in the tip and ankle links of the hair cell stereocilia. We suggest that recessive digenic inheritance involving these genes could affect the ultrastructure of the stereocilia links in familial MD.

Could ionic regulation disorders explain the overlap between meniere's disease and migraine?

Ménière's disease (MD) is an inner ear disorder characterized by a burden of symptoms and comorbidities, including migraine. In both disorders, ionic dysregulation may play a role as a predisposing factor. In recent years. aquaporins have been widely investigated, but the results are far from conclusive. We recently studied the genetics of ionic transporters and the hormone endogenous ouabain as predisposing factors for development of MD. In particular, we found two genetic polymorphisms associated with MD: 1) rs3746951, a missense variant (Gly180Ser) in the salt-inducible kinase-1 (SIK1) gene encoding a Na+, K+ ATPase; 2) rs487119, an intronic variant of gene SLC8A1 coding for a Na+, Ca++ exchanger (NCX-1). Ionic concentration in the brain also plays a role in the pathophysiology of migraine. In this brief review we summarize what has been published on MD and migraine.

MicroRNA Profiling as a Methodology to Diagnose Ménière's Disease: Potential Application of Machine Learning.

OBJECTIVE: Diagnosis and treatment of Ménière's disease remains a significant challenge because of our inability to understand what is occurring on a molecular level. MicroRNA (miRNA) perilymph profiling is a safe methodology and may serve as a "liquid biopsy" equivalent. We used machine learning (ML) to evaluate miRNA expression profiles of various inner ear pathologies to predict diagnosis of Ménière's disease. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary academic hospital. SUBJECTS AND METHODS: Perilymph was collected during labyrinthectomy (Ménière's disease, n = 5), stapedotomy (otosclerosis, n = 5), and cochlear implantation (sensorineural hearing loss [SNHL], n = 9). miRNA was isolated and analyzed with the Affymetrix miRNA 4.0 array. Various ML classification models were evaluated with an 80/20 train/test split and cross-validation. Permutation feature importance was performed to understand miRNAs that were critical to the classification models. RESULTS: In terms of miRNA profiles for conductive hearing loss versus Ménière's, 4 models were able to differentiate and identify the 2 disease classes with 100% accuracy. The top-performing models used the same miRNAs in their decision classification model but with different weighted values. All candidate models for SNHL versus Ménière's performed significantly worse, with the best models achieving 66% accuracy. Ménière's models showed unique features distinct from SNHL. CONCLUSIONS: We can use ML to build Ménière's-specific prediction models using miRNA profile alone. However, ML models were less accurate in predicting SNHL from Ménière's, likely from overlap of miRNA biomarkers. The power of this technique is that it identifies biomarkers without knowledge of the pathophysiology, potentially leading to identification of novel biomarkers and diagnostic tests.

Systematic Review of Sequencing Studies and Gene Expression Profiling in Familial Meniere Disease.

Familial Meniere Disease (FMD) is a rare inner ear disorder characterized by episodic vertigo associated with sensorineural hearing loss, tinnitus and/or aural fullness. We conducted a systematic review to find sequencing studies segregating rare variants in FMD to obtain evidence to support candidate genes for MD. After evaluating the quality of the retrieved records, eight studies were selected to carry out a quantitative synthesis. These articles described 20 single nucleotide variants (SNVs) in 11 genes (FAM136A, DTNA, PRKCB, COCH, DPT, SEMA3D, STRC, HMX2, TMEM55B, OTOG and LSAMP), most of them in singular families-the exception being the OTOG gene. Furthermore, we analyzed the pathogenicity of each SNV and compared its allelic frequency with reference datasets to evaluate its role in the pathogenesis of FMD. By retrieving gene expression data in these genes from different databases, we could classify them according to their gene expression in neural or inner ear tissues. Finally, we evaluated the pattern of inheritance to conclude which genes show an autosomal dominant (AD) or autosomal recessive (AR) inheritance in FMD.

Burden of Rare Variants in the OTOG Gene in Familial Meniere's Disease.

OBJECTIVES: Meniere's disease (MD) is a rare inner ear disorder characterized by sensorineural hearing loss, episodic vertigo, and tinnitus. Familial MD has been reported in 6 to 9% of sporadic cases, and few genes including FAM136A, DTNA, PRKCB, SEMA3D, and DPT have been involved in single families, suggesting genetic heterogeneity. In this study, the authors recruited 46 families with MD to search for relevant candidate genes for hearing loss in familial MD. DESIGN: Exome sequencing data from MD patients were analyzed to search for rare variants in hearing loss genes in a case-control study. A total of 109 patients with MD (73 familial cases and 36 early-onset sporadic patients) diagnosed according to the diagnostic criteria defined by the Barany Society were recruited in 11 hospitals. The allelic frequencies of rare variants in hearing loss genes were calculated in individuals with familial MD. A single rare variant analysis and a gene burden analysis (GBA) were conducted in the dataset selecting 1 patient from each family. Allelic frequencies from European and Spanish reference datasets were used as controls. RESULTS: A total of 5136 single-nucleotide variants in hearing loss genes were considered for single rare variant analysis in familial MD cases, but only 1 heterozygous likely pathogenic variant in the OTOG gene (rs552304627) was found in 2 unrelated families. The gene burden analysis found an enrichment of rare missense variants in the OTOG gene in familial MD. So, 15 of 46 families (33%) showed at least 1 rare missense variant in the OTOG gene, suggesting a key role in familial MD. CONCLUSIONS: The authors found an enrichment of multiplex rare missense variants in the OTOG gene in familial MD. This finding supports OTOG as a relevant gene in familial MD and set the groundwork for genetic testing in MD.

Current status on researches of Meniere's disease: a review.

Background: Meniere's disease (MD) is a complex and multifactorial inner ear disease. The etiology of MD is unclear. Significant progress had been made in diagnosis and treatment. Complete cure for this disease is still impossible.Objectives: This review covers the updated research results in MD in the past decades.Material and methods: Recent publications were critically reviewed.Results: The relationship between Endolymphatic hydrops and Meniere symptoms requires further study. Direct visualization of EH is achieved by special sequences of inner ear MRI. Appearance of EH could be observed in MD patients both in symptomatic and asymptomatic ears. Visualization of EH in vivo might make a great substantial improvement in diagnose of MD. The first goal of the management of MD is to reduce the attack frequency. Several safe and effective medical and surgical therapies are practiced to help patients to control vertigo and preserve hearing.Conclusions and significance: There has been no major breakthrough in the pathogenesis research of MD in recent years. Visualization of EH in vivo might make a great substantial improvement in diagnose of MD. Clinicians still have few effective ways to alleviate the progress of the disease.