The influence of mitochondrial biological function on sudden sensorineural hearing loss: Exploring potential mechanisms and associations through Mendelian randomization analysis

Recently, observational studies have reported an association between renal function and sudden sensorineural hearing loss (SSNHL), but the causal relationship remains unclear. To begin with, we filtered single nucleotide polymorphisms from genome-wide association studies at the summary level by implementing quality control measures in genome-wide association studies databases. Afterwards, we employed a two-sample Mendelian randomization (MR) analysis to indirectly evaluate the causal effect of renal function indicators on the risk of SSNHL. Finally, a multivariate MR approach was conducted to account for potential interactions among the positive findings. MR analysis was performed using several methods, including inverse variance weighting (IVW), maximum likelihood, weighted median, MR-Egger regression, and penalized weighted median. In addition, this study included individuals who underwent routine medical examinations at Dongzhimen Hospital, Beijing University of Chinese Medicine, from September 2004 to September 2024, and employed propensity score methodology to assess the potential causal relationship between renal function and SSNHL. In the IVW method, a significant causal relationship was found between urinary albumin excretion (UAER) and cystatin-C (Cys-C) and the risk of SSNHL (via IVW random effects: UAER [odds ratios [ORs] 0.239, 95% confidence intervals [CI] 0.071–0.813, P-value .022]; via IVW-fixed effects: UAER [OR 0.239, 95% CI 0.082–0.698, P-value .009]; Cys-C [OR 0.824, 95% CI 0.712–0.955, P-value .010]). These findings remained consistent in multivariate MR analysis, which accounted for mutual adjustments. (via IVW: UAER [OR 0.343, 95% CI 0.119–0.991, P value .048]; Cys-C [OR 0.808, 95% CI 0.697–0.936, P value .0005]). Additionally, our case–control study revealed a significant trend towards elevated Cys-C and reduced serum uric acid in patients with SSNHL. There appears to be a causal relationship between renal function and SSNHL, particularly the levels of UAER, Cys-C and serum uric acid. These findings imply that renal function should be specifically focused on in the prevention and treatment of SSNHL.

Diabetes mellitus is closely associated with sudden sensorineural hearing loss (SSNHL), but no definitive evidence has established a causal relationship between type 1 diabetes mellitus (T1DM) and SSNHL. This study aims to investigate the impact of T1DM on SSNHL from a genetic perspective, providing insights for risk prediction and treatment strategies. Genetic data related to exposure (T1DM) and outcome (SSNHL) were obtained from publicly available genome-wide association studies (GWAS). Instrumental variables were selected, and Mendelian randomization (MR) analysis was conducted to explore the causal association between T1DM and SSNHL. Inverse variance weighted (IVW) analysis was used as the primary method, with random-effects IVW serving as the main analytical approach. MR-Egger, weighted median, simple mode, and weighted mode analyses were utilized as supplementary methods. Cochran's Q test was applied to evaluate the heterogeneity of the selected instrumental variables, MR-PRESSO was applied to detect outliers, MR-Egger regression was used to assess horizontal pleiotropy and leave-one-out analysis was conducted to examine the robustness of individual single nucleotide polymorphisms (SNPs) on the overall results. A total of 127 SNPs were selected as instrumental variables for the MR analysis. IVW analysis demonstrated a genetically determined association between T1DM and SSNHL (OR=1.036, 95% CI 1.002 to 1.071, P=0.038). Forest plots and scatter plots indicated a causal relationship, suggesting that T1DM increases the risk of SSNHL. Cochran's Q test demonstrated no significant heterogeneity among SNPs (MR-Egger: Q=126.030, P=0.356; IVW: Q=126.450, P=0.373). The funnel plot appeared symmetrical, indicating that the selected instrumental variables were primarily related to exposure rather than potential confounding factors. The MR-Egger intercept was not significantly different from zero (P=0.527), indicating no evidence of horizontal pleiotropy among the SNPs. MR-PRESSO analysis did not identify any outlier SNPs (P=0.356). Leave-one-out analysis confirmed the robustness of the findings, as the results remained stable after removing individual SNPs. Two-sample MR analysis supports the conclusion that T1DM patients have an increased risk of developing SSNHL.

Among patterns of hearing loss, sudden sensorineural hearing loss (SSNHL) ranks as one of the least common, accounting for 1% of all cases of hearing loss with approximately 4000 new cases reported each year (1). However, the inability to prepare for the sudden loss of function, the lack of a satisfying explanation for its cause, and the limited treatment options also make it a particularly devastating disorder. A specific cause for the hearing loss is found in less than 15% of cases and guidelines for management of SSNHL have only recently been published (2,3). Prior association studies have shown that traditional vascular risk factors such as smoking, hypertension, dyslipidemia, and diabetes can be risk factors for SSNHL, with one study even showing a higher risk of subsequent stroke in patients with SSNHL (4). However, meta-analyses have shown that these associations are also inconsistent (5). Although a history of migraine is not generally considered to be a risk factor for SSNHL, it has also not been systematically investigated. Case reports have indicated that some patients who experience SSNHL also experience other symptoms attributable to migraine and that sudden hearing loss associated with a severe migraine headache can be associated with ischemic changes in the inner ear (6,7). In this volume, Chu et al. report on the association between migraine and the incidence of SSNHL over a 10-year period using the National Health Insurance Research Database in Taiwan, which is based on a universal health care system with centralized information on all diagnostic codes and prescriptions. The study was designed as a retrospective case-control study, with the incidence of SSNHL in migraine patients and controls in the year 2000 used as the baseline. Migraine and SSNHL were both diagnosed by ICD9-CM codes, as were major vascular risk factors such as diabetes, hypertension, dyslipidemia, and atrial fibrillation. After exclusion of a history of SSNHL at baseline, Meniere’s disease, and acoustic neuromas, 10,280 migraine patients were compared to 41,120 controls. These subjects were followed for a median of five years until one of three outcomes was obtained: 1) development of SSNHL, 2) subject death, or 3) end of the study in 2009. The study required that the diagnosis of migraine be coded by a neurologist and that the diagnosis of SSNHL be coded by an otolaryngologist. The authors report a 1.8-fold increased risk of SSNHL in patients with migraine with a very small but detectable cumulative risk of SSNHL each year throughout the 10 years of observation. This cumulative risk amounted to 0.4% in migraine patients and 0.2% in controls. In a multivariate analysis, comorbidity with hypertension increased the risk to 1.92 in migraine patients, but this was not statistically significant. The role of hypertension in the risk of SSNHL in controls was not reported, however. The study provides a global perspective on the incidence of SSNHL. The authors calculated an incidence of 81.6 cases in 100,000 person-years in migraine subjects and 45.7 cases per 100,000 person-years in controls. The relative risk increased to 118.6 per 100,000 person-years in migraine subjects over the age of 40 years. These estimates are much higher than the often-reported incidence of five to 20 cases in 100,000 person-years for SSNHL (2,3,5). However, some widely cited incidence data in the current literature are extrapolated from as few as 18 patients cared for in one health care system or are reported frompersonal communications (8,9). Older studies also did not use the current, more generally accepted criteria for SSNHL that require a loss of 30 dBof hearing in three consecutive frequencies occurring over less than 72 hours. Conversely, the reported incidence in the study was lower than the 160 per 100,000 person-years reported in 2004 from a German population (10). One challenge to making an accurate assessment of the incidence of SSNHL in any setting is that acuity can often be difficult to determine, especially if the patient recovers quickly. Between one-third and two-thirds of

Assessing causal relationship between non-alcoholic fatty liver disease and risk of atrial fibrillation

Decision letter: Common genetic variations in telomere length genes and lung cancer: a Mendelian randomisation study and its novel application in lung tumour transcriptome

Editor's evaluation: Common genetic variations in telomere length genes and lung cancer: a Mendelian randomisation study and its novel application in lung tumour transcriptome

Lipids and sudden sensorineural hearing loss: A bidirectional two-sample Mendelian randomization analysis

Numerous compelling epidemiological studies have linked air pollution to Sudden Sensorineural Hearing Loss (SSNHL). However, the causal relationship behind this association has not yet been established. We employed a Two-Sample Mendelian Randomization (MR) approach to investigate the causal relationship between air pollution (nitrogen dioxide, nitrogen oxides, PM2.5, PM10, and PM2.5-10) and SSNHL.Independent genetic variants associated with air pollution and SSNHL were selected as instrumental variables (IVs) at a genome-wide significance level. All summary data were obtained from GWAS databases. The primary method used for MR analysis was the Inverse Variance Weighted (IVW) method, supplemented by various MR analyses method, including weighted median, simple mode, weighted mode, and MR-Egger, to ensure robustness. Cochran's Q test was employed for heterogeneity assessment. To identify potential pleiotropy, we utilized MR-Egger regression and the MR-PRESSO global test. Additionally, sensitivity analyses were performed using the leave-one-out approach. The MR analysis using the IVW method showed no substantial evidence supporting a direct causal relationship between air pollution and the risk of SSNHL (Nitrogen dioxide: P = 0.488, Nitrogen oxides: P = 0.572, PM2.5: P = 0.480, PM10: P = 0.225, and PM2.5-10: P = 0.608). There was no evidence of heterogeneity or pleiotropy, and sensitivity analyses based on the leave-one-out approach indicated that individual single nucleotide polymorphisms (SNPs) did not affect the robustness of the results.This study found no substantial evidence to support a causal relationship between air pollution and the risk of SSNHL in the European population.

Poststroke sudden sensorineural hearing loss (SSNHL) can hinder communication between patients and healthcare professionals, thereby restricting participation in rehabilitation programs and limiting improvements in physical performance. However, the relationship between stroke and SSNHL remains unclear. This study employed a nationwide population-based dataset to investigate the relationship between stroke and SSNHL.The Taiwan Longitudinal Health Insurance Database was used to compile data from 11,115 stroke patients and a comparison cohort of 33,345 matched nonstroke enrollees. Each patient was followed for 5 years to identify new-onset SSNHL. Stratified Cox proportional-hazard regression analysis was used to examine the association of stroke with subsequent SSNHL.Among the 44,460 patients, 66 patients (55,378 person-years) from the stroke cohort and 105 patients (166,586 person-years) from the comparison cohort were diagnosed with SSNHL. The incidence of SSNHL was approximately twice as high among stroke patients than among nonstroke patients (1.19 and 0.63/1000 person-years, respectively). Stroke patients had a 71% increased risk of SSNHL, compared with nonstroke patients (adjusted hazard ratio [HR] 1.71, 95% confidence interval [CI] 1.24–2.36). We also observed a remarkable increase in risk of SSNHL in stroke patients within 1-year of follow-up (adjusted HR 5.65, 95% CI 3.07–10.41) or under steroid therapy during hospitalization (adjusted HR 5.14, 95% CI 2.08–12.75).Patients with stroke had a higher risk of subsequent SSNHL compared with patients without stroke. In particular, stroke patients within 1-year follow-up and those undergoing steroid therapy during hospitalization should be treated with the utmost caution, considering that the risk of SSNHL increases by more than 5-fold.

BackgroundObservational studies have indicated a potential association between thyroid dysfunction and the risk of sudden sensorineural hearing loss (SSNHL). However, the precise causal relationship between the two remains uncertain. The objective of our study was to assess the causal influence of thyroid function on SSNHL by employing a bidirectional and multivariable Mendelian randomization (MR) approach.MethodsSingle-nucleotide polymorphisms (SNPs) associated with free thyroid (FT4) and thyroid stimulating hormone (TSH) were selected from the summary data of a large genome-wide association study (GWAS) conducted on European individuals. The summary-level data of SSNHL were also obtained from a GWAS, which included 196,592 participants (1,491 cases and 195,101 controls). The MR analysis primarily utilized the inverse variance weighted (IVW) method, with sensitivity analyses performed using the weighted median, MR-Egger, and MR-PRESSO approaches.ResultsIn the IVW method, an elevated genetically predicted FT4 level was found to effectively reduce the risk of SSNHL (OR = 0.747, 95% CI = 0.565–0.987, P = 0.04). These findings were consistent when conducting multivariate MR analysis, which adjusted for TSH levels (OR = 0.929, 95% CI = 0.867–0.995, P = 0.036). However, genetically predicted TSH levels did not emerge as a risk factor for SSNHL (OR = 1.409, 95% CI = 0.895–1.230, P = 0.547). Furthermore, even after adjusting for FT4 levels in the multivariate MR analysis, no evidence of a direct causal relationship between TSH levels and the risk of SSNHL was observed (OR = 1.011, 95% CI = 0.880–1.161, P = 0.867). The reverse MR analysis showed that there was no evidence of a direct causal relationship between SSNHL and the risk of FT4 level (OR = 1.026, 95% CI = 0.999–1.054, P = 0.056) or TSH level (OR = 1.002, 95% CI = 0.989–1.015, P = 0.702).ConclusionWithin the normal range, genetic variants associated with higher FT4 levels demonstrate a potential protective effect against SSNHL, whereas there is no direct causal relationship between TSH levels and the risk of SSNHL.

Patients with sudden sensorineural hearing loss (SSNHL) may lose their hearing. The relationship between SSNHL and total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels is still unclear. The association of TC, TG, HDL-C, and LDL-C levels with the risk and prognosis of SSNHL was explored in this study. After searching for literature in different databases, 13 researches were used to summarize the risk and prognosis of SSNHL associations with TC, TG, HDL-C, and LDL-C using meta-analysis. Total cholesterol had a significant association with the risk of SSNHL (95% CI, 1.34-2.91). Adjustment for confounding factors and grouping criteria of TG were all significant sources of heterogeneity. One of the significant sources of heterogeneity in the LDL-C subgroup analyses was an adjustment for confounders. Sensitivity analysis revealed a robust association between TC and the risk of SSNHL. There was a significant publication bias in the association between TC and SSNHL prognosis High TC level is a risk factor for SSNHL.

Dose-response relationship of aspirin and sudden sensorineural hearing loss risk in type 2 diabetes: Aspirin dosage on SSNHL risk in T2D.

: Protein kinase C-eta (PRKCH) gene has been recently identified as a susceptible risk locus for cerebral infarction and hemorrhage in the Asian populations. The inner ear artery, a usual branch of anterior inferior cerebellar artery, is an end artery with minimal collaterals, therefore, the inner ear is particularly vulnerable to ischemia. The potential association between the development of stroke and sudden sensorineural hearing loss (SSNHL) has been implied. The authors hypothesized that the PRKCH polymorphism predisposing to stroke is associated with SSNHL risk, in view of brain magnetic resonance imaging (MRI) findings. The authors compared 33 cases of prevalent SSNHL with other cases among 2188 adults aged 40 to 79 years who participated in the Study of Aging, to assess the impact of PRKCH 1425G/A polymorphism in consideration of brain MRI findings. Multiple logistic regression was used to obtain odds ratios (ORs) for SSNHL, with adjustment for other possibly influential factors under additive model of minor allele. The per-allele OR for SSNHL risk was 1.770 (95% confidence interval: 1.024–3.060) after adjustments. The effect of the 1425A-allele varied by white matter lesion (WML) status. A significant impact of the A-allele on SSNHL risk increment was observed in higher-WML group, but not in no- or mild-WML group. The 1425A-allele of PRKCH has probably contributed to the susceptibility to SSNHL, despite the etiological heterogeneity of SSNHL, and the impact of the PRKCH 1425A variation observed in this study may imply underlying vascular pathogenesis of SSNHL.

The etiologies of idiopathic sudden sensorineural hearing loss (SSNHL) and Ménière's disease remain unclear. Recently, accumulating evidence has demonstrated that free radicals are related to the pathology of inner ear disease. Because genetic factors may contribute partly to the etiologies of SSNHL and Ménière's disease, we investigated the association between genetic polymorphisms located in genes related to the free-radical process and susceptibility to SSNHL and Ménière's disease. We compared 83 patients affected by SSNHL and 83 patients affected by Ménière's disease with 2048 adults (for SSNHL) and 1946 adults (for Ménière's disease) who participated in the National Institute for Longevity Sciences, Longitudinal Study of Aging. Multiple logistic regression was used to calculate odds ratios (ORs) for SSNHL and Ménière's disease in individuals with polymorphisms in the genes: methionine synthase (MTR; rs1805087); methionine-synthase reductase (MTRR; rs1801394); nitric oxide synthase 3 (NOS3; rs1799983); caveolin 1 (Cav1; rs3840634); melatonin receptor 1B (MTNR1B; rs1387153); NAD(P)H oxidase p22(phox) subunit (NADH/NADPHp22phox; rs4673); and mitochondria 5178 (MT5178; rs28357984). The NOS3 polymorphism was significantly associated with a risk of SSNHL; in addition, the OR for the NOS3 polymorphism and SSNHL risk was 2.108 (CI, 1.343–3.309) with adjustment for age and sex. The Cav1 polymorphism was significantly associated with a risk of Ménière's disease; moreover, the OR for the Cav1 polymorphism and Ménière's disease risk was 1.849 (CI, 1.033–3.310) with adjustment for age and sex. In conclusion, the NOS3 and Cav1 polymorphisms were significantly associated with the risk of SSNHL and Ménière's disease, respectively.

ObjectiveSudden hearing loss is a frightening symptom that often prompts an urgent or emergent visit to a health care provider. It is frequently, but not universally, accompanied by tinnitus and/or...