Regulation of Fn14 Receptor and NF-κB Underlies Inflammation in Meniere’s Disease

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.

Update on Vertigo in Autoimmune Disorders, from Diagnosis to Treatment

“…Potential sites of this inflammatory damage are the blood–brain barrier, the endolymphatic sac, the spiral ligament, and the reticular lamina in the neurosensory epithelium of the cochlea. Patients with this genotype have been shown to develop bilateral Menière disease through a mediated NF- κ B inflammatory response [ 37 ].…”

Current Understanding and Clinical Management of Meniere's Disease: A Systematic Review

“…This variant is also found in up to 18% of patients with autoimmune conditions. 12 Also, glucocorticoids and other immunosuppressants in MD patients with clinical response support the immune dysfunction hypothesis. 38…”

“…[27][28][29][30] The MD Consortium in Europe led to a multicenter study on MD genetics. 4,12 The genetic hypothesis of MD relies on different facts, like the variability of its prevalence depending on ethnic background, the familial aggregation studies, 4 and the identification of several genes in autosomal dominant familial MD, including COCH, FAM136A, DTNA, PRKCB, DPT, and SEMA3D in exome sequencing studies. 5,6,31 However, as the condition is rare, twin studies are lacking.…”

“…11 An allelic variant has been identified in 6p21.33 (leading signal rs4947296) associated with bilateral MD. 12 So, certain MD patients with this genetic marker should be considered as autoimmune MD. 13 The relationship between MD and both respiratory and food allergies has been reported.…”

TRAIL, OPG, and TWEAK in kidney disease: biomarkers or therapeutic targets?

“…Generally, the activation of the TWEAK/Fn14 pathway is strictly dependent on Fn14 up-regulation. In normal (healthy) conditions, both TWEAK and Fn14 appear to be expressed at low levels; by contrast, in various disease conditions, including autoimmune and inflammatory/neuro-inflammatory diseases [82][83][84][85][86][87] as well as several types of cancer [88][89][90][91][92][93], both Fn14 and TWEAK expressions are up-regulated.…”