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Front Immunol. 2017 Dec 13;8:1739. doi: 10.3389/fimmu.2017.01739. eCollection 2017.

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

Author information

1
Otology and Neurotology Group CTS495, Department of Genomic Medicine - Centre for Genomics and Oncological Research - Pfizer/Universidad de Granada/Junta de Andalucía (GENYO), Granada, Spain.
2
Computational Biology Group, Luxembourg Centre for Systems Biomedicine (LCSB), Universite du Luxembourg, Belval, Luxembourg.
3
Group of Genetics of Complex Diseases, Department of Genomic Medicine - Centre for Genomics and Oncological Research - Pfizer/Universidad de Granada/Junta de Andalucía (GENYO), Granada, Spain.
4
Department of Otolaryngology, Complexo Hospitalario de Pontevedra, Pontevedra, Spain.
5
Department of Otolaryngology, Hospital Universitario Salamanca, IBSAL, Salamanca, Spain.
6
Department of Otolaryngology, Hospital Universitario de Gran Canaria Dr Negrin, Las Palmas de Gran Canaria, Las Palmas, Spain.
7
Department of Otolaryngology, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospital Universitario Virgen de las Nieves, Granada, Spain.
8
Department of Otolaryngology, Hospital Miguel Servet, Zaragoza, Spain.
9
Department of Otorhinolaryngology, Hospital Universitario Vall d'Hebron, Barcelona, Spain.
10
Department of Otorhinolaryngology, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, Spain.
11
Department of Otorhinolaryngology, Centro Hospitalar de S.João, EPE, University of Porto Medical School, Porto, Portugal.
12
Department of Otolaryngology, Hospital Universitario de Getafe, Getafe, Madrid, Spain.
13
Department of Otolaryngology, Clínica Universidad de Navarra, Pamplona, Spain.
14
Department of Otorhinolaryngology, Hospital Universitario de Cabueñes, Gijón, Asturias, Spain.
15
Department of Otorhinolaryngology, Hospital La Fe, Valencia, Spain.
16
Division of Otoneurology, Department of Otorhinolaryngology, Complexo Hospitalario Universitario, Santiago de Compostela, Spain.
17
Department of Otorhinolaryngology, Instituto Antolí Candela, Madrid, Spain.
18
Division of Otoneurology, Department of Otorhinolaryngology, Complejo Hospitalario Badajoz, Badajoz, Spain.
19
Unit of Chronic Inflammatory Diseases, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
20
Luxembourg Centre for System Biomedicine (LCSB), Universite du Luxembourg, Belval, Luxembourg.

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.

KEYWORDS:

Meniere’s disease; NF-κB signaling; NFKB1; TNFRSF12A; TWEAK/Fn14 pathway; sensorineural hearing loss; vertigo

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