Abstract
Meniere's disease is an episodic vestibular syndrome associated with sensorineural hearing loss (SNHL) and tinnitus. Patients with MD have an elevated prevalence of several autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis and psoriasis), which suggests a shared autoimmune background. Functional variants of several genes involved in the NF-κB pathway, such as REL, TNFAIP3, NFKB1 and TNIP1, have been associated with two or more immune-mediated diseases and allelic variations in the TLR10 gene may influence bilateral affectation and clinical course in MD. We have genotyped 716 cases of MD and 1628 controls by using the ImmunoChip, a high-density genotyping array containing 186 autoimmune loci, to explore the association of immune system related-loci with sporadic MD. Although no single nucleotide polymorphism (SNP) reached a genome-wide significant association (p<10−8), we selected allelic variants in the NF-kB pathway for further analyses to evaluate the impact of these SNPs in the clinical outcome of MD in our cohort. None of the selected SNPs increased susceptibility for MD in patients with uni or bilateral SNHL. However, two potential regulatory variants in the NFKB1 gene (rs3774937 and rs4648011) were associated with a faster hearing loss progression in patients with unilateral SNHL. So, individuals with unilateral MD carrying the C allele in rs3774937 or G allele in rs4648011 had a shorter mean time to reach hearing stage 3 (>40 dB HL) (log-rank test, corrected p values were p = 0.009 for rs3774937 and p = 0.003 for rs4648011, respectively). No variants influenced hearing in bilateral MD. Our data support that the allelic variants rs3774937 and rs4648011 can modify hearing outcome in patients with MD and unilateral SNHL.
Highlights
Meniere’s disease (MD) is a chronic disorder affecting the inner ear characterized by fluctuating sensorineural hearing loss (SNHL), episodes of vertigo, tinnitus, and aural fullness and it can affect both ears in 10–40% of cases [1]
Several mechanisms may explain the development of immunemediated inner ear disease (IED): a) cross-reactions with a crossreactive epitope as suspected for some inflammatory diseases [3], b) damage to the inner ear caused by proinflammatory cytokines such as IL-1B [4], [5] or TNF [6] as in some autoimmune diseases, or c) inappropriate immune response or intolerance to harmless unrecognized substances combined with genetic factors that modify the immune response as in allergies [2]
We found no evidence of population stratification in the principal component analysis (PCA)
Summary
Meniere’s disease (MD) is a chronic disorder affecting the inner ear characterized by fluctuating sensorineural hearing loss (SNHL), episodes of vertigo, tinnitus, and aural fullness and it can affect both ears in 10–40% of cases [1]. Some evidence support this hypothesis including the response to steroids therapy, the finding of elevated levels of autoantibodies or circulating immune complexes (CIC) in the serum of some patients with MD against inner ear antigens and the association of allelic variants of MHC class I polypeptiderelated sequence A (MICA) and Toll-like receptor 10 (TLR10, rs11096955) gene with hearing loss progression in patients with MD [7], [8].
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