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Regulation of Fn14 Receptor and NF-κB Underlies Inflammation in Meniere's Disease
Lidia Frejo1, Teresa Requena1, Satoshi Okawa2
1Otology and Neurotology Group CTS495, Department of Genomic Medicine - Centre for Genomics and Oncological Research - Pfizer/Universidad de Granada/Junta de Andalucía (GENYO), Granada, Spain.
Abstract:
Meniere's disease (MD) is a rare disorder characterized by episodic vertigo, sensorineural hearing loss, tinnitus, and aural fullness. It is associated with a fluid imbalance between the secretion of endolymph in the cochlear duct and its reabsorption into the subarachnoid space, leading to an accumulation of endolymph in the inner ear. Epidemiological evidence, including familial aggregation, indicates a genetic contribution and a consistent association with autoimmune diseases (AD). We conducted a case-control study in two phases using an immune genotyping array in a total of 420 patients with bilateral MD and 1,630 controls. We have identified the first locus, at 6p21.33, suggesting an association with bilateral MD [meta-analysis leading signal rs4947296, OR = 2.089 (1.661-2.627); p = 1.39 × 10-09]. Gene expression profiles of homozygous genotype-selected peripheral blood mononuclear cells (PBMCs) demonstrated that this region is a trans-expression quantitative trait locus (eQTL) in PBMCs. Signaling analysis predicted several tumor necrosis factor-related pathways, the TWEAK/Fn14 pathway being the top candidate (p = 2.42 × 10-11). This pathway is involved in the modulation of inflammation in several human AD, including multiple sclerosis, systemic lupus erythematosus, or rheumatoid arthritis. In vitro studies with genotype-selected lymphoblastoid cells from patients with MD suggest that this trans-eQTL may regulate cellular proliferation in lymphoid cells through the TWEAK/Fn14 pathway by increasing the translation of NF-κB. Taken together; these findings suggest that the carriers of the risk genotype may develop an NF-κB-mediated inflammatory response in MD.
Insights
Researchers identified a genetic link to Meniere's disease (MD), a rare inner ear disorder. A specific gene region (6p21.33) and the TWEAK/Fn14 inflammatory pathway are implicated in MD development.
Area of Science:
- Genetics
- Immunology
- Otolaryngology
Background:
- Meniere's disease (MD) is a rare inner ear disorder causing vertigo, hearing loss, tinnitus, and aural fullness.
- MD is linked to endolymph fluid imbalance and shows familial aggregation, suggesting genetic and autoimmune factors.
- Autoimmune diseases (AD) share inflammatory pathways potentially relevant to MD.
Purpose of the Study:
- To identify genetic loci associated with bilateral Meniere's disease (MD).
- To investigate the functional role of identified genetic variants in MD pathogenesis.
- To explore potential therapeutic targets by examining inflammatory pathways.
Main Methods:
- A two-phase case-control study utilizing an immune genotyping array with 420 MD patients and 1,630 controls.
- Analysis of gene expression profiles (trans-eQTL) in peripheral blood mononuclear cells (PBMCs).
- Signaling pathway analysis and in vitro studies on lymphoblastoid cells.
Main Results:
- The first genetic locus associated with bilateral MD was identified at 6p21.33 (rs4947296, P = 1.39 × 10⁻⁹).
- This locus acts as a trans-eQTL in PBMCs, implicating the TWEAK/Fn14 pathway (P = 2.42 × 10⁻¹¹).
- The TWEAK/Fn14 pathway, known in AD, may regulate lymphoid cell proliferation via NF-κB in MD.
Conclusions:
- Genetic factors contribute to Meniere's disease, with a significant association at 6p21.33.
- The TWEAK/Fn14 inflammatory pathway is a key player in MD pathogenesis.
- An NF-κB-mediated inflammatory response in carriers of the risk genotype may underlie MD development.