Objective: Summarize and analyze the current research results of tinnitus-related genes, explore the potential links between the results of each study, and provide reference for subsequent studies. Methods: Collect and sort out the research literature related to tinnitus genes included in PubMed, Web of Science, China National Knowledge Infrastructure, and Wanfang Data Knowledge Service Platform before December 31, 2019. Then the relevant contents of the literature were sorted out and summarized. Results: Fifty-one articles were finally selected for analysis: 31 articles (60.8%) were classified as researches on animal models of tinnitus, and 20 (39.2%) as researches on tinnitus patients. Existing studies have shown that genes related to oxidative stress, inflammatory response, nerve excitation/inhibition, and nerve growth are differentially expressed in tinnitus patients or animal models, and have presented the potential links between genes or proteins in the occurrence and development of tinnitus. Conclusion: The research on tinnitus-related genes is still in the exploratory stage, and further high-quality research evidence is needed.

Keywords: Gene, molecular pathway, review, tinnitus

How to cite this article:
Li Zc, Fang Bx, Yuan Lx, Zheng K, Wu Sx, Zhong N, Zeng Xl. Analysis of Studies in Tinnitus-Related Gene Research. Noise Health 2021;23:95-107
  Introduction 

Tinnitus is a subjective auditory experience that occurs in the absence of external sounds or electrical stimulation. Tinnitus has a prevalence rate, between 10% and 19% of adults,[1] and as the mechanisms involved in its occurrence and development are not yet fully understood, there is still no effective treatment for this global public health problem. In recent years, studies on the occurrence and development of tinnitus have continually increased, but how tinnitus occurs, and how it affects the normal life of patients is not completely understood. Although many risk factors related to tinnitus have been identified, such as hearing loss, noise exposure, and so on,[2] not all individuals exposed to these risk factors develop tinnitus. Moreover, tinnitus is a subjective psychologic experience. Therefore, currently there is no objective assessment indicator to determine whether it exists, and the extent of its impact on patients’ mental health.

Genes are the basic hereditary units that control biologic traits, affecting all aspects of life including birth, aging, illness, and death. They are the intrinsic factors that determine health. Therefore, the genetic traits of the individual may determine whether an individual exposed to some risk factors may develop tinnitus or not. With the rapid advancement of genome sequencing technology and the cross-application of bioinformatics and big data science, the relationship between genes and human diseases has attracted increasing amounts of attention. The role of heredity in tinnitus has long been the focus of researchers. In 2007, a multicenter familial aggregation study provided the first support for the influence of heredity on tinnitus. A total of 198 families (981 research subjects) were enrolled in the study. The familial aggregation of tinnitus was analyzed using a variety of methods including mixed model, familial correlation, and risk prediction. It was found that tinnitus demonstrated significant family aggregation and the familial correlation was 0.15.[3] Subsequently, survey data (with a sample size of 51,574) from Norway’s Nord–Trøndelag health screening suggested that after removing family environmental factors, although the heritability ceiling was only 0.11, heredity played an important role in the occurrence of tinnitus.[4] In 2017, two studies on twins, once again confirmed the importance of heredity in tinnitus. Bogo et al.[5] followed a group of male twins and found that identical twins had higher tinnitus occurrence than fraternal twins (baseline: 0.46 vs. 0.07; follow-up: 0.51 vs. 0.32), whereas the influence of individual-specific environment was 0.56 to 0.61, suggesting a moderate genetic contribution to tinnitus. Maas et al.[6] investigated 10,464 pairs of twins, and also found that identical twins had higher tinnitus occurrence than fraternal twins (0.32 vs. 0.20), and the heritability maybe depending on the subtype (bilateral vs. unilateral) and gender. A recent study in Sweden based on 11,060 adopted children found that children had greater risk of having a tinnitus when their biologic parents had tinnitus but not when their adoptive parents had tinnitus (odds ratio 2.22 vs. 1.00, respectively).[7] With the genetic predisposition to tinnitus becoming more and more obvious, the exploration of tinnitus-related genes has also received attention from the researchers.[8],[9],[10],[11]

The earliest gene expression study on tinnitus included an animal model experiment by Wallhäusser-Franke.[12] The study found that after injection of salicylic acid in Mongolian gerbils, the expression of c-fos was increased in the pressure-related brainstem region, such as the locus coeruleus which is the gray matter around the aqueduct of midbrain, and the lateral parabrachial nucleus. It was believed that the tinnitus caused by salicylic acid was produced by the combined action of auditory and nonauditory nervous nuclei. Although c-fos was only used as a marker to reflect the activation status of the nuclei after salicylic acid injection, this study on tinnitus from the perspective of gene expression laid the foundation for future explorations. Over the past 10 years, the research on tinnitus-related genes has increased.

To specifically explore tinnitus-related genes, this study intends to review and summarize the existing research results in animals and humans. It will also indicate directions where further exploration is required. This would allow further exploration of its molecular and physiologic mechanisms and provide targets for its treatment while satisfying the needs of clinical diagnosis and scientific research.

  Materials and methods 

Step 1: identifying the research question

The purpose of this systematic review was to summarize and analyze the current research results of tinnitus-related genes, explore the potential molecular pathways of tinnitus occurrence and development, and provide reference for subsequent studies.

Step 2: identifying relevant studies

This review is based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.[13] “Tinnitus” and “Gene” were used as joint keywords, through the full text search, to search for gene-related articles on tinnitus in PubMed, Web of Science, China National Knowledge Infrastructure, and Wanfang Data Knowledge Service Platform. All literature published before December 31, 2019 were looked up to collect relevant articles. An EndNote (version X9.2; Clarivate Analytics, Boston, MA, USA) library was created.

Step 3: study selection

The literature inclusion criteria were as follows:

Research article.Research subjects were tinnitus patients or animal models with tinnitus.The study was published in the peer-reviewed journal.The study was published in English or Chinese.

The exclusion criteria of literature were as follows:

Tinnitus accompanied by Meniere disease, acoustic neuroma, and vascular nerve compression.Tinnitus accompanied by cardiovascular disease or diabetes.Objective tinnitus caused by high jugular bulb, epitympanic diverticulum, or defect.The patients suffered from other diseases that are known to induce tinnitus, such as dentinogenesis imperfecta, familial paragangliomas 1/3/4, episodic ataxia type II.[14]Studies that adopted animal models of tinnitus without clearly stating whether the model was successful.

Step 4: data charting

The following data were extracted from animal model studies: author, year of publication, animal species, treatment methods, location of materials, and main outcomes reported.

The following data were extracted from patient studies: author, year of publication, object, gender, age, and main outcomes reported.

Step 5: collating, summarizing, and reporting the results

Data were descriptively summarized according to the following data items:

Basic numerical analysis.Summary of findings.   Results 

Basic numerical analysis

We collected a total of 764 articles from the four databases using a full-text search. Based on the inclusion and exclusion criteria and excluding repetitive content, 51 articles were finally selected for analysis [Figure 1]: 31 articles (60.8%) were classified as researches on animal models of tinnitus, and 20 (39.2%) as researches on tinnitus patients. The vast majority (90.2%) of the articles were published in the last 10 years [Figure 2].

Summary of findings

Studies of animal model

Animal model of tinnitus mainly observed the gene or protein expression differences during the development of tinnitus. Most studies established by salicylic acid (74.20%), whereas a small number used noise (19.35%) or cell-phone radiation exposure (6.45%). Different regions of the auditory pathway were studied, as well as some nonauditory systems [Table 1].

A total of 36 differentially expressed genes or proteins have been discovered, mainly involved in physiologic processes such as nerve excitation or inhibition, nerve repair, inflammatory response, and oxidative stress. Genes or proteins related to the inflammatory response, neural excitation, and nerve repair were upregulated, whereas genes or proteins involved in neural inhibition and neural protection were downregulated [Figure 3].

Studies of patient

Patient-based studies focused primarily on patients with chronic tinnitus (30% for both subjective and undescribed studies). The elderly (20%), noise environmental workers (10%), hearing impaired patients (5%), and radiotherapy patients (5%) were also studied and analyzed. A total of 24 differentially expressed genes or proteins have been investigated, mainly involved in physiologic processes such as nerve repair, nerve excitation or inhibition, and inflammatory response [Figure 4]. Seven of the studies suggested that some gene polymorphisms may be involved in the formation or development of tinnitus, whereas six studies did not find any relationship between gene polymorphisms and tinnitus, including BDNF and GDNF. The remaining articles mainly discuss the protein markers of tinnitus and the role of mitochondrial DNA (mtDNA) in tinnitus development [Table 2].

Figure 4 Functional classification of differentially expressed genes in tinnitus patients.

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Comprehensive analysis

Studies on the animal models and patients suggesting that oxidative stress and the inflammatory response of the nervous system are likely to be the pathophysiologic basis of tinnitus. This led us to learn the potential links between genes or proteins in the occurrence and development of tinnitus [Figure 5]: (1) damage to the inner ear tissue due to noise exposure, ototoxic drugs[66],[67] or ischemia leads to the release of O2-; (2) the highly expressed Mn-SOD protein rapidly converts O2- into H2O2. However, due to the low expression of CAT, a key antioxidant enzyme in the body’s defense against oxidative stress, H2O2 is not promptly lysed into H2O and O2, resulting in an increased accumulation of H2O2, which aggravates the inner ear tissue damage; (3) as an immune response, the damaged inner ear tissue recruits a large number of neutrophils, macrophages, and helper T lymphocytes, resulting in the release of a large number of inflammatory factors such as interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-α)[68]; (4) TNF-α activates the nuclear factor kappa B pathway through TNFR1 and TNFR2,[69] promoting the continuous build-up of inflammatory factors such as TNF-α, IL-1β, and IL-6 and leading to more severe inflammation of the inner ear; (5) inflammatory factors such as TNF-α, which are continuously expressed in the peripheral nervous system, cause dysfunction of the blood–brain barrier, and enter the central nervous system[70] stimulating the microglia and astrocytes to further secrete more inflammatory factors including TNF-α and IL-1β, leading to inflammation of the central nervous system.

Figure 5 The potential links between genes or proteins in the occurrence and development of tinnitus.

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Meanwhile, studies have also shown that genes associated with neural excitation/inhibition, such as NR2B, CR1, DR1, TRPV1, OTOF, KCC2, etc., were also differentially expressed in the peripheral and central nervous systems, suggesting that abnormal discharge caused by inflammation of the nervous system could be the direct cause of tinnitus: (1) TNF-α and IL-1β promote high expression of NR2B and TRPV1, respectively, and increased the excitability of the nervous system; (2) the high expression of genes related to neuroexcitability such as DR1, OTOF, KCC2 and the low expression of genes related to neuroinhibition such as CR1 also contribute to the increased excitability of the nervous system. As a result, damage to inner ear tissues causes an increase in the excitability of peripheral and central nervous system through oxidative stress and inflammatory response, which provides a pathophysiologic basis for tinnitus formation.

Finally, genes related to postinjury repair of the nervous system and synapse formation, such as Arg3.1, Gap-43, and c-fos, were also differentially expressed, suggesting that cortical remodeling might occur in the central nervous system of patients with tinnitus and the functional connections between various cortices of the brain might have changed, leading to not only the chronicity of tinnitus, but also a series of psychologic and behavioral problems for the patient.

  Discussion 

Tinnitus is a global public health problem, and the mechanisms involved in its development and impact on the individuals have not yet been clearly determined. With the ongoing research on the genetic predisposition to tinnitus and the rapid development of genome sequencing and bioinformatic analysis, understanding the molecular pathways and genes involved in the development of tinnitus has gradually become an important aspect of tinnitus research. This study has comprehensively summarized the research status of tinnitus-related genes by reorganizing the published research studies. The quality of the existing published literature is poor, especially the research based on tinnitus animal model. However, considering that there are still relatively few researches on tinnitus-related genes, it is hoped that the induction and analysis of these literature can provide certain reference for future research.

Current research on tinnitus patients has identified genotypes of several genes that may be associated with tinnitus induced by noise exposure, such as KCNE1, IL-6, and TNFα[47],[49],[53],[59] or with the level of tinnitus distress, such as SLC6A4, ADD1, GRM7, and NAT2.[46],[55],[58] Differential expression of many genes (or proteins) was also found in animal models of tinnitus. The existing research with tinnitus animal models and patients with tinnitus has found a number of genes with differential expression and polymorphisms, and help to further understand the occurrence, development, and persistence of tinnitus. Most of the studies are still in the primary stage; however, they have mainly focused on the relationship between the differential gene expression or polymorphism and tinnitus, and lack of systematic discussion on gene function, upstream and downstream regulatory genes, and their regulatory mechanisms, which fails to further clarify why these genes have changed, and the role of these changes in gene in the entire process of tinnitus. In addition, the genes discussed in previous studies are mainly related to the occurrence of tinnitus (through tinnitus animal model), but less related to the development and persistence.

First, the studied genes were mainly selected based on hypothesis driven, namely genes that they believed might be related to tinnitus. It is not definite that the selected genes are specific for tinnitus, and only a limited number of studies have been conducted. In addition, comprehensive identification of genes related to tinnitus has not been achieved, and errors in disease–gene association may also be expected. For example, SLC6A4, a gene that shows an association with tinnitus severity,[46] has been widely studied to be associated with the risk of depression, but not be found to be significantly associated with depression in a recent large-scale study.[71] Similarly, different studies have shown inconsistent results for BDNF, which had been considered a potential molecular marker for tinnitus. The allele frequencies of BDNF do not differ significantly between the tinnitus patients and normal controls,[50],[57] but the combination of BDNF and GDNF genotypes might have a certain predictive value for symptom severity in female tinnitus patients.[73] Meanwhile, statistically significant differences were detected in the BDNF CpG6 and GDNF CpG3-5-6 methylation ratios between the control group and the chronic tinnitus patients, supporting the relationship between the promoter methylations of BDNF/GDNF genes and tinnitus.[67] However, the relationship between BDNF expression and the severity of tinnitus is still controversial. Some studies found that the BDNF concentration in the tinnitus group was higher than that in the normal control group,[64] but others have found otherwise.[56] Some studies have found that the BDNF levels were not related to the severity of tinnitus,[50] whereas some others have shown that BDNF concentration in the mild tinnitus group was higher than that in the severe tinnitus and the normal control groups.[73] As we know, BDNF prevents neuronal damage and apoptosis, improves the pathologic state of neurons, and promotes the regeneration and differentiation of neurons after injury, damage to the auditory nervous system is an important pathologic basis of tinnitus. The change in BDNF expression in tinnitus patients may reflect the repair process after an auditory system injury (the aforementioned BDNF study on patients with tinnitus, did not include details of the duration of tinnitus, and did not rule out interference of repair after injury), rather than being directly related to tinnitus. Therefore, the tinnitus-related genes, which were suggested by current research, need to be further explored and substantiated.

Secondly, the inner ear and brain tissues of the animal tinnitus models are important materials for current research, which are helpful for exploring changes in gene expression in the nervous system during the process of tinnitus. However, at present, tinnitus animals are mainly modeled by salicylic acid injection and noise exposure, which is not completely consistent with the real clinical tinnitus pathologic mechanism. In addition, tinnitus in animals is mainly assessed by their behavioral and electrophysiologic changes. It is not yet clear whether these changes are due to tinnitus or simply an animal’s stress response. More importantly, many existing research designs of tinnitus animals still have deficiencies, such as the lack of strict exclusion criteria (some studies use differences between groups as an indicator of tinnitus production, rather than individual animals), and the lack of blind evaluation of the results. Therefore, it is necessary to fully understand the potential influence of various factors on experimental results before using animal models for tinnitus research, and to reduce the interference of irrelevant factors through more rigorous experimental design. The existing research results of tinnitus animals provide an important reference for our follow-up research, but it still needs further analysis and discussion in application.

Thirdly, the study of tinnitus patients can more directly understand the role of genes in clinical tinnitus and provide reference for the formulation of clinical diagnosis of tinnitus. However, the existing studies were mainly conducted in the Caucasian population, and the sample sizes in these studies were relatively small. In addition, there was no strict distinction in various clinical phenotypes. Therefore, further studies need to focus on the genetic differences between races or regions and improve the quality of research results by expanding sample sizes. Meanwhile, genome-wide association studies have suggested that tinnitus is affected by multiple single-nucleotide polymorphisms (SNPs) and not just one, and many prominent SNPs are located in noncoding regions,[72] but existing studies in tinnitus have mainly focused on SNPs in coding RNA. As noncoding RNA (ncRNA) also affects the expression of coding RNA, thereby influencing normal biologic functions, the role of ncRNAs in the occurrence, development, and persistence of tinnitus must be considered in future research.

Finally, this review integrated the relatively independent research findings into a relatively unified arrangement, so as to facilitate the reference of subsequent studies and better predict the possible role of each gene or protein in the occurrence or development of tinnitus, and hence to promote the further research. However, it is worth noting that tinnitus and hearing loss are mainly caused by auditory system damage, which are closely related and independent. As existing research schemes have not been able to distinguish tinnitus from auditory system damage and hearing loss, it is not clear whether the differentially expressed genes or proteins found in existing studies are the key to the formation and development of tinnitus, which needs further exploration and clarification.

  Conclusion 

In summary, the number of research articles on tinnitus-related genes has been on the rise, and their contents and research methods are also gradually diversifying. Several genes have been found to be associated with oxidative stress and inflammatory response in the animal tinnitus models. In addition, several gene polymorphisms in patients with tinnitus have been found to be related to the risk of tinnitus after noise exposure, enriching the knowledge of tinnitus-related genes. These have presented the potential links between genes or proteins in the occurrence and development of tinnitus. However, the quality of the included literature is uneven, the sample size included in the study was small, the race of the subjects was single, and the division of clinical manifestations of tinnitus was not clear, and the relationship between these genes and tinnitus remains unclear. The pathways through which these genes cause the occurrence and development of tinnitus are also unclear. Therefore, in the future genetic research on tinnitus should be more rigorous, distinguish clinical subtypes, expand sample size, and pay more attention to racial differences. At the same time, further systematic screening is needed to identify tinnitus-related genes along with their functions, mechanisms, and further research would benefit their actual clinical applications.

Financial support and sponsorship

This work was funded by the Science and Technology Program of Guangzhou, China (grant number: 201704030081).

Conflicts of interest

There are no conflicts of interest.

 

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