Relationship Between Chronic Tinnitus and Glial Cell Line-Derived Neurotrophic Factor Gene rs3812047, rs1110149, and rs884344 Polymorphisms in a Turkish Population

Abstract

Glial cell line-derived neurotrophic factor (GDNF) plays a key role in early development of central auditory pathway and the inner ear. However, the auditory pathway studies of GDNF gene polymorphisms are scarce in the literature, and the studies especially associated with tinnitus are limited. Our study aimed to identify whether GDNF gene polymorphisms play any roles in the pathophysiology of tinnitus by investigating the relationship between tinnitus and GDNF polymorphisms. A total of 52 patients with chronic tinnitus and ages ranging from 18 to 55 were admitted to the Ear-Nose-Throat outpatient clinic of Celal Bayar University Medical Faculty Hospital of Manisa, Turkey and constituted the study group. Another 42 patients of the same age range, without tinnitus symptoms and lacking any systemic disease, were also admitted to the clinic and formed the control group. The tympanometric, audiological, and psychoacoustic assessments of the subjects were performed. Deoxyribonucleic acid samples obtained using venous blood taken for routine inspections were used to investigate GDNF gene polymorphisms (rs884344, rs3812047, and rs1110149) by polymerase chain reaction-based restriction fragment length polymorphism method. No correlation could be detected between GDNF rs884344 and rs3812047 polymorphisms and subjects with tinnitus (p > 0.05). Heterozygosity was significantly lower for GDNF rs1110149 polymorphism in tinnitus subjects compared to the controls (p < 0.05). However, the allele frequencies for all 3 polymorphisms were not significantly different between tinnitus and control groups (p > 0.05). Failure to detect correlations between tinnitus and GDNF gene polymorphisms suggests this may be due to the fact that the GDNF gene has a variable expression pattern in different tissues and pathologies. Therefore, the study should be improved and its scope should be expanded by including a larger group of patients and different tissues to investigate the expression pattern of GDNF.

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.…”

“…These three GDNF markers were similarly screened in a replication study including 52 Turkish patients with chronic tinnitus and 42 controls aged between 18 and 55 years (Orenay-Boyacioglu et al, 2016). No statistically significant distribution was detected in allele frequencies for all three markers between tinnitus and control groups.…”

“…No statistically significant distribution was detected in allele frequencies for all three markers between tinnitus and control groups. The only parameter reaching significance was heterozygosity (C:G) in the SNP rs1110149 ( p = 0.02, χ 2 ), that was found to have a lower frequency in tinnitus patients compared to controls (Orenay-Boyacioglu et al, 2016). …”

“…Furthermore, population differences can have drastically differing allelic architecture that can complicate the mapping of putative risk factors when attempting association replication in patients of differing ethnicities (Sharma et al, 2014). Although underpowered, even if significance were achieved in the initial association study analyzing GDNF markers in German tinnitus patients, the replication study that followed studied the same three markers in a Turkish tinnitus group (Sand et al, 2012b; Orenay-Boyacioglu et al, 2016). …”

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).…”