Autoimmune Meniere Disease

Introduction: Meniere’s disease (MD) is a set of rare disorders with a core phenotype characterized by episodic vertigo, sensorineural hearing loss, tinnitus and aural fullness. Epidemiological evidence shows a consistent association with several autoimmune diseases and cluster analysis support that an autoimmune comorbid condition could be a predictor of autoimmune MD.

Materials and methods: A case-control study using an immune genotyping array including 420 patients with bilateral MD and 1630 controls was design to search for association signals. We designed gene expression studies using homozygous genotype-conditioned peripheral blood mononuclear cells (PBMCs) from patients, and generated conditioned lymphoblastoid cell lines to investigate cellular response to tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK).

Results: We have identified a locus at 6p21.33 associated with bilateral MD (leading signal rs4947296, OR= 2.089 (1.661-2.627); p= 1.39x 10^-09). This genetic marker was found in 14% of patients with bilateral MD and 18% of patients with an associated autoimmune comorbidity. Gene expression profiles of homozygous genotype-selected individuals showed that this marker is a trans-expression quantitative trait locus (eQTL) in PBMCs and regulates several genes in the TWEAK/Fn14 pathway, leading to NF-κB-mediated inflammation. Signaling analysis predicted several TNF-related pathways, being the TWEAK/Fn14 pathway the top candidate (p= 2.42 x 10^-11). This pathway modulates inflammation in several human autoimmune diseases. In vitro studies with genotype-selected lymphoblasts from patients with MD suggest that this trans-eQTL regulates cellular proliferation in lymphoid cells through the TWEAK/Fn14 pathway by increasing the translation of NF-κB.

Conclusions:

The variant rs4947296 a genetic diagnostic marker for autoimmune MD
The receptor Fn14 and NF-κB are druggable molecules for a personalized treatment of MD.

Funding INNBIO-ADVANCE INV-007 and ISCIII PI 13/1242

Use of allelic variants in the locus 6p21.33 for the diagnosis, prognosis and treatment of Meniere’s disease. Patent P201531458, October 9, 2015.