Genetics of Meniere's disease

Timothy C. Hain, MD • Page last modified: July 18, 2022

Now that the human genome has been sequenced, there are papers emerging about genes or gene fragments (SNPs) linked to the diagnosis of Meniere's. As is the case in other disorders defined by symptoms, there are a subset of Meniere's patients, roughly 10%, where Meniere's is clearly running in their family. Unfortunately, there appear to be numerous genes in the small group of patients with familial patterns.

Genetic studies like these, as in other symptom defined disorders, point out a potential fallacy of thinking that we are dealing with a single entity. Presumably, each mutation has it's own pattern of symptoms, response (if any) to treatments, and it is naive to think that there is a homogeneous "Menieres" group -- rather there is somewhat of a spectrum. But without some grouping, it is difficult to think coherently. Kangasniema and Hiettiko commented "Studies concerning antibodies, HLA types and genetic polymorphisms have produced conflicting results and no single antibody, HLA type or polymorphism has been found in all or even in a significant subpopulation of MD patients." (2018)

When studies are done of Meniere's in a particular ethnic group (such as Chinese for example), the results may not apply to another ethnic group (such as persons of European descent). This is just the way it works in Genetic studies.

Another comment is that genetic studies are often "fishing expeditions". There are a lot of genes (fish) out there, and if you cast a big net, you are bound to catch a few, that possibly by chance, are in the group you sampled.

Reports:

Areweiler-Harbeck reported that 19% of 193 patients with Meniere's had a positive family history(2011). They suggested that chromosome 5 was a "probable" candidate region for MD. Remembering that nearly every linkage study done on Migraine came up with a different candidate region, we think it best to wait for more data.

Lee et al (2015) reported that out of a total of 286 Korean patients with Meniere's, about 9.8% had a probable family member, and 6.3% had a definite family member. This study suggests that familial Meniere's may be less common in Korea than in the rest of the world. Of course, this would be what one would expect in populations that have relatively little genetic heterogeneity.

Renuena et al (2015) reported two mutations in a single Spanish family, in FAM136A and DTNA, with "familial Meniere's". These tiny family studies mean very little by themselves -- once there are a hundred of these, there might be some conclusions to draw.

Teggi et al (2016) studied 155 patients (not very many in our opinion), and reported that 4 SNPs were different than 186 controls: Two in the SIK1 gene (salt inducible kinase-1), and 2 in the SLC8A1 gene (Na-Ca++ exchanger). Teggi et al (2021) reported on this topic again. Again, recall that genetics studies are always finding correlations, which are usually different than the next genetic study to be published. This study was of Spaniards, and of course, might not apply to -- lets say -- Chinese.

According to Roman-Narajo et al (2020), "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. "

Gallego-Martinez and Lopez-Escamez (2020) reviewed the genetics and wrote " Moreover, the genetic landscape of sporadic MD is more complex and it involves multiplex rare variants in several SNHL genes such as GJB2, USH1G, SLC26A4, ESRRB, and CLDN14 and axonal-guidance signalling genes such as NTN4 and NOX3. "

Scarp et al (2019) wrote concerning a single case, "p.Y273N was considered the more likely candidate for MD, as the gene is known to affect both hearing and vestibular function. The variant in the HMX2 gene may affect inner ear development and structural integrity and thus might predispose to the onset of MD. "

Huang et al (2019) commented about unusual sensitivity to gentamicin in Meniere's patients and wrote "Multivariate analysis revealed two SNPs, rs1052571 in caspase 9 (CASP9; p = .017) and rs3745274 in cytochrome P450 2B6 (p = .053), which were associated with susceptibility to ITG injections."

Dai et al (2019), studied Chinese, and reported "KCNE1 and KCNE3 gene mutations were, respectively, different between the SMD and FMD groups. KCNE3 gene polymorphism was key to FMD disease, whereas KCNE1 was more important to the onset of SMD." FMD means familial and SMD sporadic.

Frejo et al (2017) wrote "Signaling analysis predicted several tumor necrosis factor-related pathways, the TWEAK/Fn14 pathway being the top candidate (p = 2.42 x 10(-11)). "

Nair et al (2016) suggested that a link between vascular SNPs and Menieres, and said "Transfusion related acute lung injury (TRALI) is linked to rs2288904 and genome wide association studies link rs2288904 and rs9797861 to venous thromboembolism (VTE), coronary artery disease and stroke. Here we report linkage disequilibrium of rs2288904 with rs3087969 and the association of these SLC44A2 SNPs with Meniere's disease severity.

Martin-Sierra et al found another gene (PRKCB). They wrote "The PKCB II signal was more pronounced in the apical turn of the cochlea when compared with the middle and basal turns. It was also much higher in cochlear tissue than in vestibular tissue. Taken together, our findings identify PRKCB gene as a novel candidate gene for familial MD" This might correlate with the low-tone sensorineural hearing loss pattern in Meniere's disease.

Roman-Naranjo et al (2021) reported mutations in the MYO7A gene in familial meniere disease. They reported "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."

Molecular biology:

Lopez-Escamez et al (2018) wrote about the molecular biology of Meniere's and said "At least two mechanisms have been involved in MD: (a) a pro-inflammatory immune response mediated by interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and IL-6, and (b) a nuclear factor-kappa B (NF-kappaB)-mediated inflammation in the carriers of the single-nucleotide variant rs4947296. It is conceivable that microbial antigens trigger inflammation with release of pro-inflammatory cytokines at different sites within the cochlea, such as the endolymphatic sac, the stria vascularis, or the spiral ligament, leading to fluid imbalance with an accumulation of endolymph".

Teggi et al (2017), instead suggested that "These data support the hypothesis that a genetically induced dysfunction of ionic transport may act as a predisposing factors to develop MD."

Summary as of 2022:

Genetic studies have found a large number of genes or gene fragments in roughly 10% of patients with Meniere's disease. These studies have not yet helped clinicians treat patients, but we can hope that this will change. There does seem to be a connection to the inflammatory cytokines (IL1, TNF, IL6), which suggests that treatments which suppress these cytokines may be eventually more prevalent.

References:

  1. Arweiler-Harbeck, D., et al. (2011). "Genetic aspects of familial Meniere's disease." Otol Neurotol 32(4): 695-700.
  2. Dai, Q., et al. (2019). "The Polymorphic Analysis of the Human Potassium Channel KCNE Gene Family in Meniere's Disease-A Preliminary Study." J Int Adv Otol 15(1): 130-134.
  3. Frejo, L., et al. (2017). "Regulation of Fn14 Receptor and NF-kappaB Underlies Inflammation in Meniere's Disease." Front Immunol 8: 1739.
  4. Gallego-Martinez, A. and J. A. Lopez-Escamez (2020). "Genetic architecture of Meniere's disease." Hear Res 397: 107872.
  5. Huang, C. J., et al. (2019). "CASP9 genotype confers gentamicin susceptibility in intratympanic treatment of intractable vertigo caused by Meniere's disease." Acta Otolaryngol 139(4): 336-339.
  6. Kangasniemi, E. and E. Hietikko (2018). "The theory of autoimmunity in Meniere's disease is lacking evidence." Auris Nasus Larynx 45(3): 399-406.
  7. Lee, J. M., et al. (2015). "Genetic aspects and clinical characteristics of familial meniere's disease in a South Korean population." Laryngoscope.
  8. Lopez-Escamez, J. A., et al. (2018). "Towards personalized medicine in Meniere's disease." F1000Res 7.
  9. Martin-Sierra, C., et al. (2016). "A novel missense variant in PRKCB segregates low-frequency hearing loss in an autosomal dominant family with Meniere's disease." Hum Mol Genet 25(16): 3407-3415.
  10. Nair, T. S., et al. (2016). "SLC44A2 single nucleotide polymorphisms, isoforms, and expression: Association with severity of Meniere's disease?" Genomics 108(5-6): 201-208.
  11. Roman-Naranjo, P., et al. (2020). "Burden of Rare Variants in the OTOG Gene in Familial Meniere's Disease." Ear Hear 41(6): 1598-1605.
  12. Roman-Naranjo, P., et al. (2021). "Rare coding variants involving MYO7A and other genes encoding stereocilia link proteins in familial meniere disease." Hear Res 409: 108329.
  13. Skarp, S., et al. (2019). "Whole-exome sequencing suggests multiallelic inheritance for childhood-onset Meniere's disease." Ann Hum Genet 83(6): 389-396.
  14. Teggi, R., et al. (2017). "Genetics of ion homeostasis in Meniere's Disease." Eur Arch Otorhinolaryngol 274(2): 757-763.
  15. Teggi, R., et al. (2021). "Could ionic regulation disorders explain the overlap between meniere's disease and migraine?" J Vestib Res 31(4): 297-301.

Written By: Timothy C. Hain, MD of Chicago Dizziness and Hearing.