Abstract
Background
Sudden sensorineural hearing loss (SSNHL) is a multifactorial disease, and its etiology is still unknown. SSNHL may be caused by environmental factors and genetic changes. PCDH15 is associated with susceptibility to hearing loss. The relationship between PCDH15 and SSNHL remains unknown.
Methods
In this study, the potential association between PCDH15 polymorphism and SSNHL in Chinese population was evaluated. Two single nucleotide polymorphisms PCDH15‐rs7095441 and rs11004085 in 195 SSNHL patients and 182 healthy controls were determined by TaqMan technology.
Results
In Chinese population, the TT genotype and T allele of rs7095441 are associated with increased susceptibility to SSNHL. The relationships between rs7095441 and the degree of hearing loss were analyzed, and TT genotype increased the risk of hearing loss. Among SSNHL patients, patients with TT genotype of rs7095441 have an increased risk of vertigo.
Conclusion
This study found that the TT genotype of SNP rs7095441 can increase the risk of SSNHL in Chinese population.
Keywords: PCDH15, Rs7095441, single nucleotide polymorphisms, sudden sensorineural hearing loss, vertigo
The potential association between PCDH15 polymorphism and SSNHL in Chinese population was evaluated. Two single nucleotide polymorphisms PCDH15‐rs7095441 and rs11004085 in 195 SSNHL patients and 182 healthy controls were analyzed by PCR analysis.
1. INTRODUCTION
Sudden sensorineural hearing loss (SSNHL) refers to sensorineural hearing loss with unknown causes within 72 h. 1 Alexander found that the incidence of sudden deafness was 27 per 100,000 people, and the incidence increased with age, with more than 66,000 new cases every year. 2 The onset age of SSNHL is 50–60 years old, and there is no gender difference. Unilateral deafness is frequent, bilateral sudden deafness accounts for about 5% of all SSNHL. 3 The pathogenesis of SSNHL is unclear. The popular theories are virus infection, microcirculation disturbance or thrombosis, immunology, round window membrane rupture, genetics, and so on. Studies have reported a relationship between hearing loss and cognitive impairment. The risk of dementia in SSNHL patients is significantly higher than that in patients without SSNHL. The possible reasons are cognitive decline caused by unwillingness to communicate, lack of physical activity, and self‐social isolation after hearing loss. 4 Many neurological and psychological diseases caused by hearing loss seriously reduce the quality of life of patients. Therefore, it is urgent for clinicians to improve the cure rate of SSNHL patients quickly and effectively.
Protocadherin 15 (PCDH15) belongs to a superfamily of calcium‐dependent cell adhesion proteins, which is located at 10q21.1 and contains 39 exons. PCDH15 protein encoded by PCDH15 belongs to a subfamily of cadherin, including 11 EC domains, 1 transmembrane domain, and cytoplasmic domain. 5 , 6 , 7 Different from classical cadherin, each EC domain of pro‐cadherin is encoded by one or more exons. 8 PCDH15 initially identified the longest transcript with 33 exons encoding a protein containing 1955 amino acids. 6 , 7 According to different transcription and splicing, PCDH15 protein has three isotypes of cytoplasmic domains. The time and position of these isoforms expressed in hair cells are different, which shows that their roles in hair cells are different. PCDH15 is a cadherin expressed in inner ear hair cells, which can interact with cadherin‐23 (CDH23) in inner ear hair cells to form end junction cilia. The end junction destruction caused by the mutation of its coding gene plays an important role in sensorineural hearing loss.
As a multifactorial disease, SSNHL may be caused by environmental factors and genetic changes. Some studies have reported the association between gene polymorphism in SSNHL patients. Chien found that GPX3 polymorphism may affect the risk of SSNHL in southern Taiwan, and GG and AG genotypes of SNP rs3805435 may be the protective genotypes of SSNHL. 9 There is no report on the relationship between PCDH15 gene polymorphism and SSNHL risk. This study investigated whether PCDH15 gene polymorphism is a risk factor for SSNHL. We conducted a case–control study to investigate the role of PCDH15 single nucleotide polymorphisms (SNPs) in the pathogenesis of SSNHL.
2. METHODS AND MATERIALS
Genomic DNA was extracted from peripheral blood using standard methods. According to previous related studies, two SNPs were selected. These two SNPs include SNP rs7095441 and rs11004085 of PCDH15 gene. 10 The extracted DNA and genotyping assays were added to TaqMan universal PCR master mix (Roche, USA) according to the manufacturer's instructions. The reaction conditions of PCR were initial denaturation at 95°C for 5 minutes, followed by 35 cycles at 95°C for 30 s, 60°C for 30 s, and 72°C for 1 minute, with a final extension at 72°C for 10 min. The genotyping procedures were then performed using ABI PRISM–7500 real‐time PCR system (Applied Biosystems).
We recruited a total of 377 people in this case–control study, including 195 SSNHL patients and 182 healthy controls from the Third Affiliated Hospital of Guangxi Medical University. Patients with SSNHL were recruited according to the diagnostic criteria in the Clinical Practice Guideline: Sudden Hearing Loss from the American Academy of Otolaryngology–Head and Neck Surgery. 11 Healthy volunteers with no history of hearing loss or any hearing impairment were included in the control group. Auditory test for patients with SSNHL using a pure tone audiometer (Astera, GN Otometrics, Denmark). Pure tone hearing thresholds were assessed according to standard procedures at frequencies of 250, 500, 1000, 2000, 4000, and 8000 Hz. Pure tone threshold average (PTA) was ciphered from frequencies of 500, 1000, 2000, and 4000 Hz. The level of the individual subject's hearing loss was graded based on disparity levels against PTA, as normal hearing (<20 dB), mild hearing loss (20–40 dB), moderate hearing loss (40–70 dB), severe hearing loss (70–95 dB), or profound hearing loss (>95 dB). The audiograms were categorized into 4 patterns, which were low tone, high tone, flat, and total hearing loss pattern. This study was approved by the Ethics Committee of the Third Affiliated Hospital of Guangxi Medical University (IRB number: Y2022164). All patients have signed informed consent forms.
SPSS 19.0 (SPSS) was used for statistical analysis. The chi‐square test was used to evaluate the frequency of alleles and genotypes between case and control groups. Continuous variables were analyzed using independent t‐tests, the results of which are presented as mean ± SD. The Hardy–Weinberg equilibrium (HWE) was examined in the controls by using the chi‐squared test. Multivariate logistic regression analysis was performed to adjust for the effects of age, gender, vertigo, tinnitus, hypertension, and diabetes while assessing the genetic effects. P < .05 was considered significant.
3. RESULTS
The characteristics of the 195 SSNHL patients and the 182 controls are shown in Table 1. The mean age of the SSNHL group was 71.9 ± 5.9 years, and the mean age of the control group was 50.7 ± 14.6 years. The SSNHL group was older than the control group (P < .0001). There was no significant difference between SSNHL cases and controls on the aspect of gender. Eighty‐four SSNHL patients had vertigo (43.1%), and 65 SSNHL patients had tinnitus (33.3%). Regarding the degree of hearing loss, 51 (26.2%) patients had mild hearing loss; 96 (49.2%) patients had moderate hearing loss; 33 (16.9%) patients had severe hearing loss; and 15 (7.7%) patients had profound hearing loss. According to the main frequency affected, 47 (24.1%) patients had low‐frequency hearing loss; 74 (37.9%) patients had high‐frequency hearing loss; 61 (31.3%) patients had flat‐type hearing loss; and 13 (6.7%) patients had total hearing loss configuration. 28.2% of SSNHL patients had hypertension. 21.5% of SSNHL patients had diabetes.
TABLE 1.
The characteristics of the SSNHL patients and controls.
| Variables | Case group[%] (n = 195) | Control group[%] (n = 182) | P‐value a |
|---|---|---|---|
| Age(years) | |||
| 18–64 | 77 (39.5) | 104 (57.1) | .001 |
| ≥65 | 118 (60.5) | 78 (42.9) | |
| Mean Age(years) | 71.9 ± 5.9 | 50.7 ± 14.6 | .001 |
| Gender | |||
| Male | 90 (46.2) | 89 (48.9) | .593 |
| Female | 105 (53.8) | 93 (51.1) | |
| Hearing status | |||
| Normal <20 dB | 0 | ||
| Mild 20–40 dB | 51 (26.2) | ||
| Moderate 40–70 dB | 96 (49.2) | ||
| Severe 70–95 dB | 33 (16.9) | ||
| Profound>95 dB | 15 (7.7) | ||
| Audiometric pattern | |||
| Low | 47 (24.1) | ||
| High | 74 (37.9) | ||
| Flat | 61 (31.3) | ||
| Total | 13 (6.7) | ||
| Associated risk factors | |||
| Tinnitus | 65 (33.3) | ||
| Vertigo | 84 (43.1) | ||
| Comorbidities | |||
| Hypertension | 55 (28.2) | ||
| Diabetes | 42 (21.5) |
Chi‐squared test.
The associations of PCDH15 polymorphism at rs7095441 and rs11004085 in 195 patients and 182 controls were analyzed (Table 2). SNPs were genotyped in HWE (P > .05). The TT genotype in rs7095441 (OR = 1.841, 95%CI = 1.167–2.904, P = .009) and the T allele carrier in rs7095441 frequency (P = .001) were both significantly higher in patients than in controls. These results suggest that TT genotype and T allele of PCDH15 at rs7095441 are associated with increased susceptibility to SSNHL in the Chinese population. No significant association of rs11004085 was found with SSNHL incidence.
TABLE 2.
Distribution of PCDH15 polymorphisms at rs7095441 and rs11004085 in PCDH15 cases and controls.
| Allele/Genotype | Case group[%] (n = 195) | Control group[%] (n = 182) | OR (95%CI) b | P‐value a |
|---|---|---|---|---|
| rs7095441 | ||||
| C | 166 (42.6) | 200 (54.9) | ||
| T | 224 (57.4) | 164 (45.1) | .001 | |
| CC + CT | 39 + 88 (65.1) | 59 + 82 (77.5) | 1 c | |
| TT | 68 (34.9) | 41 (22.5) | 1.841 (1.167–2.904) | .009 |
| rs11004085 | ||||
| C | 190 (48.7) | 181 (49.7) | ||
| T | 200 (51.3) | 183 (50.3) | .782 | |
| CC + CT | 49 + 92 (72.3) | 47 + 87 (73.6) | 1 C | |
| TT | 54 (27.7) | 48 (26.4) | 0.935 (0.593–1.474) | .773 |
Note: Genotype/allele data were shown by n(%).
Chi‐squared test.
Logistic regression.
Reference group.
The TT genotype in rs7095441 (OR = 5.042, 95%CI = 1.401–18.140, P = .013) was significantly higher in patients with profound type than in patients with mild‐type (Table 3). These results suggest that TT genotype of PCDH15 at rs7095441 is associated with the hearing status of SSNHL. The TT genotype in rs7095441 (OR = 2.966, 95%CI = 1.613–5.455, P = .000) was significantly higher in patients with vertigo. The TT genotype of rs7095441 was not associated with tinnitus in SSNHL patients.
TABLE 3.
Stratification analysis of PCDH15 polymorphisms in SSNHL patients.
| Variables | CC/CT | TT | OR (95%CI) b | P a |
|---|---|---|---|---|
| Hearing status | ||||
| Normal <20 dB | 0 | 0 | ||
| Mild 20–40 dB | 33 (26.0) | 18 (26.5) | 1 c | |
| Moderate 40–70 dB | 69 (54.3) | 27 (39.7) | 0.717(0.347–1.483) | .370 |
| Severe 70–95 dB | 21 (16.5) | 12 (17.6) | 1.048(0.421–2.609) | .920 |
| Profound>95 dB | 4 (3.1) | 11 (16.2) | 5.042(1.401–18.140) | .013 |
| Associated risk factors | ||||
| Vertigo | ||||
| Positive | 43 (33.9) | 41 (60.3) | 2.966 (1.613–5.455) | .000 |
| Negative | 84 (66.1) | 27 (39.7) | 1 c | |
| Tinnitus | ||||
| Positive | 43 (33.9) | 22 (32.4) | 0.934 (0.499–1.749) | .832 |
| Negative | 84 (66.1) | 46 (67.6) | 1 c | |
| Comorbidities Hypertension | ||||
| Positive | 36 (28.3) | 19 (27.9) | 0.980 (0.509–1.888) | .952 |
| Negative | 91 (71.7) | 49 (72.1) | 1 c | |
| Diabetes | ||||
| Positive | 27 (21.3) | 15 (22.1) | 1.048 (0.513–2.140) | .897 |
| Negative | 100 (78.7) | 53 (77.9) | 1 c |
Note: Genotype/allele data were shown by n(%).
Chi‐squared test.
Logistic regression.
Reference group.
4. DISCUSSION
Although the etiology of SSNHL is unclear, it is considered to be a multifactorial disease, which may be caused by the interaction between genetic and environmental factors. A systematic review in 2019 found an association between polymorphism and SSNHL susceptibility. A total of 47 studies involving 5230 SSNHL patients and 68 genes were included to analyze and discuss the results. Polymorphisms of 26 genes, such as GPX1, SOD‐1, IL‐1A, ITGB3, PRKCH, TNF‐α, and HSP70 were associated with susceptibility to SSNHL. 12 , 13 This study investigated the relationship between two SNPs of PCDH15 and SSNHL in Chinese population and found that PCDH15 SNP rs7095441 has obvious influence on the risk of SSNHL. We observed that the TT genotype of rs7095441 is associated with an increased risk of SSNHL. There was no significant difference in SNP rs11004085 between SSNHL patients and controls. We further analyzed the relationship between rs7095441 and the degree of hearing loss, and TT genotype increased the risk of hearing loss. Among SSNHL patients, patients with TT genotype of rs7095441 have an increased risk of vertigo.
Protocadherin 15 gene (PCDH15) is a member of cadherin superfamily. 14 It encodes a complete membrane protein and mediates calcium‐dependent cell–cell adhesion. PCDH15 helps cells adhere together and plays an important role in maintaining normal retinal and cochlear function. 15 PCDH15 is expressed in inner ear cells, specialized cells in eyes, and photoreceptor cells in retina. The exact function of PCDH15 in retina has not been completely determined. PCDH15 interacts with proteins Cadherin 23, USH2A, and VLGR1, anchored by harmonin, SANS, or whirlin and makes synaptic membranes closely adhere to homologous or heterotypic interactions with their extracellular regions. 16 The mutation of this gene is associated with nonsyndromic hearing loss and Usher syndrome (USH1F). It is reported that a single nucleotide polymorphism rs7095441 in PCDH15 is associated with NIHL risk in the European population. 10
Compared with mild‐type, the TT genotype in rs7095441 (OR = 5.042, 95%CI = 1.401–18.140, P = .013) was significantly higher in patients with profound type. PCDH15 gene is a member of cadherin superfamily. A potential biological function of PCDH15 is to mediate calcium‐dependent cell–cell adhesion and to maintain normal retinal and cochlear functions. 14 Mutations in this gene can lead to hearing loss and USH1F. In 2009, Koning reported that SNP rs7095441 of PCDH15 gene was related to the increased risk of NIHL in Swedish and Polish populations. 10 The gene span is close to 1 Mb, and the corresponding ORF is 7021 bp. The intron size of PCDH15 is as high as 150 kb, and the first three exons of this gene cover 0.42 Mb. The six breakpoint intervals are located in introns of 22 to 140 kb in size, which are located in the first third of the gene. Because of the large size of PCDH15, especially the coding ratio is very low, mainly at the 5′end of the gene, it is not surprising that large deletions with different breakpoints form a significant proportion of PCDH15 mutations. 17 Missense mutation of PCDH15 conserved sequence may change the spatial morphology of protein EC domain and disturb the interaction between PCDH15 and CDH23, which destroys the integrity of apical junction, weakens the interaction between static cilia and abnormal mechanical gating channel, resulting in deafness. 14 , 18 Chien investigated the relationship between six SNPs of the NR3C1 gene and the outcomes of SSNHL in a Taiwanese population and found that NR3C1 has an evident genetic effect on the outcomes of SSNHL. The significant result stemmed from the rs17100289 polymorphisms of the NR3C1 gene, highlighting the role this rare TT genotype of rs17100289 has in the protection against SSNHL in Taiwan. 19
Sudden deafness can occur at all ages. This study found that patients over 65 years old have a higher probability of SSNHL. With the increase of age, the function of body organs degenerates and the compliance of blood vessel wall decreases. With the increase of chronic diseases and microcirculation disturbance, the risk of poor prognosis of sudden deafness increases. 20 The mean age of the SSNHL group was 71.9 ± 5.9 years. But, the mean age of most SSNHL study was younger than 70 years old. Tian found that the mean age of SSNHL was 50.7 ± 16.7. 21 The age difference between SSNHL group and control group may be due to the selection bias.
Vertigo is a clinical manifestation of vestibular dysfunction. Our study found that the probability of vertigo in patients with sudden deafness was 43.1%. Analysis showed that patients with TT genotype had an increased risk of vertigo (OR = 2.966, 95%CI = 1.613–5.455, P = .000). The nutrient vessels of cochlea and vestibule come from labyrinthine artery, and the common cochlear artery supplying cochlea branches off vestibular cochlear artery supplying vestibule. When blood supply disorder occurs in any vessel, besides hearing loss symptoms, vertigo is often accompanied by vestibular involvement. When vestibular function is examined in patients with vertigo, vestibular organs near cochlea are often involved first, and the heavier the hearing loss, the more extensive the vestibular lesions are. 22
There are some limitations in this study. First of all, we did not determine the expression level of PCDH15 in peripheral blood and did not analyze its function. Therefore, we cannot draw a conclusion about the influence of these polymorphisms on cytokine levels. Secondly, due to the small number of SSNHL patients participating in the study, we cannot draw strong conclusions to explain the different effects among different subgroups. Third, in this study, we did not examine other predisposing factors that may lead to SSNHL, such as hyperlipidemia. Therefore, it is necessary to conduct extensive research on various potential factors of SSNHL in order to clarify its etiology.
In conclusion, we demonstrated an association between PCDH15 gene polymorphism and susceptibility to SSNHL. Our results suggest that PCDH15 is a susceptibility gene for SSNHL in Chinese population. However, resource‐intensive studies using genome‐wide association, gene–gene, gene–environment, and large‐scale association studies are needed to further clarify the molecular mechanism of SSNHL and the possible complex interactions between PCDH15 gene polymorphism and other susceptible factors of SSNHL. The results provide information for further understanding of the pathogenesis of SSNHL.
AUTHOR CONTRIBUTIONS
Shihua Yin designed the experiment. Ying Lan, Tao Hou, Lu Peng, and Yongpeng Li collected samples and conducted the study. Shihua Yin and Ying Lan analyzed the data. Ying Lan wrote the article. All the authors read and approved the article.
FUNDING INFORMATION
This study was funded by the National Natural Science Foundation of China (82,160,213, U22A2022) and the Guangxi Health Department Research Project (Z‐A20221135).
CONFLICT OF INTEREST STATEMENT
The authors declare that there are no conflicts of interest regarding the publication of this article.
ACKNOWLEDGMENTS
This study was supported by the National Natural Science Foundation of China (82160213, U22A2022) and the Guangxi Health Department Research Project (Z‐A20221135).
Lan Y, Hou T, Peng L, Li Y, Yin S. The association of genetic polymorphisms in protocadherin 15 with sudden sensorineural hearing loss in a Chinese population. J Clin Lab Anal. 2023;37:e24896. doi: 10.1002/jcla.24896
DATA AVAILABILITY STATEMENT
All of the data used to support the findings of this study are available from the corresponding author upon request.
REFERENCE
- 1. Prince ADP, Stucken EZ. Sudden sensorineural hearing loss: a diagnostic and therapeutic emergency. J Am Board Fam Med. 2021;34(1):216‐223. [DOI] [PubMed] [Google Scholar]
- 2. Alexander TH, Harris JP. Incidence of sudden sensorineural hearing loss. Otol Neurotol. 2013;34(9):1586‐1589. [DOI] [PubMed] [Google Scholar]
- 3. Chen YS, Emmerling O, Ilgner J, Westhofen M. Idiopathic sudden sensorineural hearing loss in children. Int J Pediatr Otorhinolaryngol. 2005;69(6):817‐821. [DOI] [PubMed] [Google Scholar]
- 4. Tai SY, Shen CT, Wang LF, Chien CY. Association of sudden sensorineural hearing loss with dementia: a nationwide cohort study. BMC Neurol. 2021;21(1):88. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Zhang X, Liu Y, Zhang L, et al. Genetic variations in protocadherin 15 and their interactions with noise exposure associated with noise‐induced hearing loss in Chinese population. Environ Res. 2014;135:247‐252. [DOI] [PubMed] [Google Scholar]
- 6. Ahmed ZM, Riazuddin S, Aye S, et al. Gene structure and mutant alleles of PCDH15: nonsyndromic deafness DFNB23 and type 1 usher syndrome. Hum Genet. 2008;124(3):215‐223. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Ahmed ZM, Riazuddin S, Bernstein SL, et al. Mutations of the protocadherin gene PCDH15 cause usher syndrome type 1F. Am J Hum Genet. 2001;69(1):25‐34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Doucette L, Merner ND, Cooke S, et al. Profound, prelingual nonsyndromic deafness maps to chromosome 10q21 and is caused by a novel missense mutation in the usher syndrome type IF gene PCDH15. Eur J Hum Genet. 2009;17(5):554‐564. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Chien CY, Huang TY, Tai SY, et al. Glutathione peroxidase 3 gene polymorphisms and the risk of sudden sensorineural hearing loss. Kaohsiung J Med Sci. 2017;33(7):359‐364. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Konings A, Van Laer L, Wiktorek‐Smagur A, et al. Candidate gene association study for noise‐induced hearing loss in two independent noise‐exposed populations. Ann Hum Genet. 2009;73(2):215‐224. [DOI] [PubMed] [Google Scholar]
- 11. Stachler RJ, Chandrasekhar SS, Archer SM, et al. Clinical practice guideline: sudden hearing loss. Otolaryngol Head Neck Surg. 2012;146(3 Suppl):S1‐S35. [DOI] [PubMed] [Google Scholar]
- 12. Gao Y, Wang HY, Guan J, et al. Genetic susceptibility study of Chinese sudden sensorineural hearing loss patients with vertigo. Curr Med Sci. 2021;41(4):673‐679. [DOI] [PubMed] [Google Scholar]
- 13. Cao Z, Gao J, Huang S, et al. Genetic polymorphisms and susceptibility to sudden sensorineural hearing loss: a systematic review. Audiol Neurootol. 2019;24(1):8‐19. [DOI] [PubMed] [Google Scholar]
- 14. Kazmierczak P, Sakaguchi H, Tokita J, et al. Cadherin 23 and protocadherin 15 interact to form tip‐link filaments in sensory hair cells. Nature. 2007;449(7158):87‐91. [DOI] [PubMed] [Google Scholar]
- 15. Sotomayor M, Weihofen WA, Gaudet R, Corey DP. Structural determinants of cadherin‐23 function in hearing and deafness. Neuron. 2010;66(1):85‐100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Kremer H, van Wijk E, Märker T, Wolfrum U, Roepman R. Usher syndrome: molecular links of pathogenesis, proteins and pathways. Hum Mol Genet. 2006;15:R262‐R270. [DOI] [PubMed] [Google Scholar]
- 17. Le Guédard S, Faugère V, Malcolm S, et al. Large genomic rearrangements within the PCDH15 gene are a significant cause of USH1F syndrome. Mol Vis. 2007;13:102‐107. [PMC free article] [PubMed] [Google Scholar]
- 18. Ahmed ZM, Riazuddin S, Ahmad J, et al. PCDH15 is expressed in the neurosensory epithelium of the eye and ear and mutant alleles are responsible for both USH1F and DFNB23. Hum Mol Genet. 2003;12(24):3215‐3223. [DOI] [PubMed] [Google Scholar]
- 19. Chien CY, Tai SY, Li KH, et al. Glucocorticoid receptor (NR3C1) genetic polymorphisms and the outcomes of sudden sensorineural hearing loss. J Otolaryngol Head Neck Surg. 2023;52(1):13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Chen C, Shi G, He M, et al. Characteristics and prognosis of idiopathic sudden sensorineural hearing loss in aged people: a retrospective study. Acta Otolaryngol. 2019;139(11):959‐965. [DOI] [PubMed] [Google Scholar]
- 21. Tian G, Zhang S, Yang J. Coexistence of IL‐6 ‐572C/G and ICAM‐1 K469E polymorphisms among patients with sudden sensorineural hearing loss. Tohoku J Exp Med. 2018;245(1):7‐12. [DOI] [PubMed] [Google Scholar]
- 22. Fujimoto C, Egami N, Kinoshita M, Sugasawa K, Yamasoba T, Iwasaki S. Involvement of vestibular organs in idiopathic sudden hearing loss with vertigo: an analysis using oVEMP and cVEMP testing. Clin Neurophysiol. 2015;126(5):1033‐1038. [DOI] [PubMed] [Google Scholar]
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Data Availability Statement
All of the data used to support the findings of this study are available from the corresponding author upon request.