Research Article: Intronic Variants in the NFKB1 Gene May Influence Hearing Forecast in Patients with Unilateral Sensorineural Hearing Loss in Meniere’s Disease

Date Published: November 14, 2014

Publisher: Public Library of Science

Author(s): Sonia Cabrera, Elena Sanchez, Teresa Requena, Manuel Martinez-Bueno, Jesus Benitez, Nicolas Perez, Gabriel Trinidad, Andrés Soto-Varela, Sofía Santos-Perez, Eduardo Martin-Sanz, Jesus Fraile, Paz Perez, Marta E. Alarcon-Riquelme, Angel Batuecas, Juan M. Espinosa-Sanchez, Ismael Aran, Jose A. Lopez-Escamez, David R. Booth.

http://doi.org/10.1371/journal.pone.0112171

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.

Partial Text

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]. The etiology and pathogenesis remain unknown, although one-third of MD cases may have an aberrant response of the adaptive or innate immune system, the immunological mechanisms involved have not been investigated [2].

Table 2 compares the basic clinical features of 716 patients with uni and bilateral MD in our series. As we expected, patients with bilateral SNHL had a longer duration of disease (p = 1.5×10−5), worse hearing loss at diagnosis (p = 0.003) and worse hearing stage (p = 3×10−6), a higher frequency of Tumarkin crises (p = 0.001) and autoimmune disease comorbidities (p = 0.003). However, no differences were observed in the age of onset or frequency of migraine between patients with uni or bilateral SNHL.

MD is probably a syndrome including a heterogeneous group of patients with an immune-mediated disease and non-immune mediated mechanisms. The 1995 clinical definition of the AAO-HNS does not discriminate these clinical variants [15].

Allelic variants rs3774937 and rs4648011 can modify hearing outcome in patients with MD and unilateral SNHL. A patent application number P201430716 has been submitted to the Spanish Patent and Trademark Office.

 

Source:

http://doi.org/10.1371/journal.pone.0112171