Analysis of inner ear potassium recycling genes as potential factors associated with tinnitus

Abstract

Tinnitus is defined as a perception of sound in the absence of an external acoustic stimulus. Several factors are known to influence tinnitus, e.g. hearing loss, noise exposure, age, and hypertension. As only certain individuals develop tinnitus in the presence of the above risks and in approximately 50% of cases tinnitus is not attributed to any particular cause, the question arose whether this inter-individual susceptibility to tinnitus could be explained by the influence of genetic factors. Objectives: To test the hypothesis that genetic variability in genes of the potassium recycling pathway is associated with increased susceptibility to tinnitus. Materials and Methods: The study group consisted of 626 subjects exposed to occupational noise (128 with tinnitus and 498 without tinnitus). 99 single nucleotide polymorphisms were investigated in 10 genes involved in the potassium recycling pathway in the inner ear, previously selected as putative noise-induced hearing loss (NIHL) candidate genes. Results: Nominally significant associations were obtained for 2 variants in KCNE1 (potassium voltage-gated channel, Isk-related family, member 1) and SLC12A2 (solute carrier family 12, member 2) genes. The first gene contributed to tinnitus that developed independently of hearing loss, while the second one was associated with increased susceptibility to noise-induced hearing loss. Conclusions: Present findings lend support to the notion of potassium recycling pathway genes as possible risk modifiers of tinnitus in individuals with and without hearing loss. Due to the lack of replication in other independent populations these results should be seen as suggestive.

Genetics of Tinnitus: Still in its Infancy

“…Tinnitus candidate gene selection has included genes enriched in cardiovascular function ( ACE, ADD1 ), neurotrophic factors ( BDNF, GDNF ), ion recycling pathways ( KCNE1, KCNE3, SLC12A2 ), GABA B receptor subunit ( KCTD12 ), and serotonin receptor/transporter ( HTR1A, SLC6A4 ) function. Presently, nine case-control studies have examined a combined total of 18 genes that are summarized in Table 2 (Kleinjung et al, 2006; Deniz et al, 2010; Sand et al, 2010, 2011, 2012a,b; Pawełczyk et al, 2012; Orenay-Boyacioglu et al, 2016; Yüce et al, 2016). For brevity, we describe selected case-control association studies with potentially significant results.…”

“…PCR-RFLP: polymerase chain reaction-restriction fragment length polymorphism; VNTR: variable number tandem repeat The study from Pawełczyk et al also included the analysis of eight further genes involved in the potassium recycling pathway (GJB1, GJB2, GJB3, GJB4, GJB6, KCNJ10, KCNQ1, KCNQ4) but results were not significant (Pawełczyk et al, 2012) .…”

Angiotensin-Converting Enzyme (ACE) I/D and Alpha-Adducin (ADD1) G460W Gene Polymorphisms in Turkish Patients with Severe Chronic Tinnitus

“…In another study, authors investigated the effect of acute and chronic salicylate treatment on the expression of NR2B, Arg3.1, and Egr-1 in an animal model of tinnitus, and they found both mRNA levels and the protein expression of NR2B and Arg3.1 increased in rats that were chronically administered salicylate [33] . In a study conducted with inner ear potassium recycling genes, significant associations were observed for two variants in KCNE1 and one SLC12A2 gene [34] . Furthermore, Sand et al [35] reported that GDNF genotypes together with BDNF genotypes predict tinnitus severity in women but not in men.…”

Role of inheritance in tinnitus: it is time to search the genome

“…Este tipo de estudio sólo permite identificar variantes ligadas a un gen concreto y requieren estudios a escala genómica previa para proponer genes candidatos. Por otra parte, la selección de variantes puede presentar un sesgo de selección, por la asociación entre el marcador genético en estudio y la variante genética de riesgo verdadera (desequilibrio de ligamiento), resultando difícil determinar cuál es la variante que confiere el riesgo para la fenotipo (21) Hasta ahora se han realizado 9 estudios de casos-control con 18 genes candidatos (10)(11)(12)(13)(22)(23)(24)(25)(26). (Tabla 1).…”