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|Year : 2013
: 15 | Issue : 64 | Page
|Interleukin-1β gene polymorphism and hearing loss related to the history of occupational noise exposure in Brazilian elderly
Luiz C. L. Carvalho1, Luciana L. M. Marchiori2, Juliana J Melo2, Sandra M Maciel3, Regina C Poli-Frederico1
1 Department of Molecular Biology - Centre of Research in Health Sciences, University of Northern Parana, Londrina-PR, Brazil
2 Department of Audiology and Speech Therapy, University of Northern Parana, Londrina-PR, Brazil
3 Department of Pediatric Dentistry, Dental School, Maringa State University, Maringá - Paraná, Brazil
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|Date of Web Publication||21-May-2013|
Hearing loss is the most common sensory impairment in older people, and may have social and psychological consequences, such as social isolation, frustration and depression. Noise-induced hearing loss (NIHL) is an interaction of both genetic and environmental factors. Some studies have led to the identification of possible NIHL susceptibility genes. The aim of the present study was to investigate whether the polymorphism of the interleukin (IL)-1β gene at position + 3954 was associated with complaints of hearing loss due to occupational exposure. The sample was composed of elderly people with hearing loss (age ≥ 60 years) divided into two groups: 99 with occupational exposure to noise and 193 without exposure. Information on occupational exposure to noise was obtained through interviews using a semi-structured questionnaire. Hearing acuity was measured from 500 to 6000 Hz and the IL-1β genotype was obtained by the polymerase chain reaction- restriction fragment length polymorphism technique. Differences in allelic and genotypic frequencies, and the association between genotypic frequencies and complaints of hearing loss due to occupational exposure, were analyzed by the Chi-square test at the 5% significance level. Fifty-one percent of the elderly were homozygous for the ancestral allele (C), 17.2% were homozygous for the polymorphic allele (T) and 31.8% were heterozygous. The frequency was found to be 67-33% C to allele T. There was no significant association between polymorphism in gene IL-1β and hearing loss associated with occupational exposure (χ2 = 0.538; P = 0.676). No association was found with the polymorphism of the IL-1β +3954 C/T gene and hearing loss associated with the occupational noise exposure history.
Keywords: Elderly, genetic polymorphism, hearing loss, Interleukin-1β, noise
|How to cite this article:|
Carvalho LC, Marchiori LL, Melo JJ, Maciel SM, Poli-Frederico RC. Interleukin-1β gene polymorphism and hearing loss related to the history of occupational noise exposure in Brazilian elderly. Noise Health 2013;15:160-4
|How to cite this URL:|
Carvalho LC, Marchiori LL, Melo JJ, Maciel SM, Poli-Frederico RC. Interleukin-1β gene polymorphism and hearing loss related to the history of occupational noise exposure in Brazilian elderly. Noise Health [serial online] 2013 [cited 2019 Sep 15];15:160-4. Available from: http://www.noiseandhealth.org/text.asp?2013/15/64/160/112363
| Introduction|| |
Life expectancy is increasing, especially in developing countries.  The number of Brazilians aged over 60 years increased from 2 million in 1950 to 15.4 million in 2002, a 700% increase.  Although the World Health Organization's criteria for considering an individual to be elderly is over 65 years of age, the Brazilian Health Ministry has determined that old age begins at 60 years,  probably because the Brazilian life expectancy is lower than those of the developed countries. 
With increasing longevity, the incidence of chronic diseases also increases, compromising the quality of life of elderly patients with such affections. A study conducted in São Paulo, Brazil, by Lima et al.  found that 70% of the population above 60 years of age or more had at least one chronic degenerative disease, and of these 25% have three or more of these manifestations. The same study indicated that stroke, depression and anxiety were the conditions that predominantly affect quality of life among the elderly.
Hearing loss is the most widespread sensory impairment in the elderly,  and may lead to depression, social isolation and frustration.  The most common types of hearing loss are presbycusis (aging process) and noise-induced hearing loss (NIHL), usually occurring as a result of occupational exposure.  The NIHL is irreversible and may have several symptoms such as hearing loss complaint, tinnitus, vertigo and a gradual decrease or distortion in speech comprehension.  Previous studies have shown that hearing loss affects about 60% of the elderly population living in Brazil.  Among adults, several studies have shown a range from 15.9% to 48% in the NIHL prevalence  and 11.6% in the elderly aged over 80 years. 
NHIL is associated with overexposure to intense sound, but it also has a genetic component,  and, recently, the induction of inflammatory responses and up-regulation of pro-inflammatory cytokines in the inner ear has been reported in noise over-stimulation. 
The structure and expression of cytokines can be influenced by genetic variation, resulting in pathogenic conditions,  and several studies have examined the single nucleotide polymorphisms (SNPs) as risk factors for inflammatory diseases.  These SNPs may affect the expression, secretion and cellular transport of the interleukin (IL)-1β protein; , they may also decrease the level of IL-1 receptor antagonist (IL-1Ra), which increases the production and activities of IL-1β. 
IL-1 is a polypeptide consisting of subtypes IL-1α and IL-1β. The IL-1 gene is located on the log arm of chromosome 2.  The IL-1β gene consists of seven exons, six introns, and 1498 bp, responsible for encoding a 269 amino acid protein. IL-1β is the predominant IL-1 form, and it is secreted mainly by macrophages, dendritic cells, monocytes, natural killers, and B cells. The IL-1β gene polymorphism (+3954 C/T) may cause a 4-fold increase in IL expression, increasing the catabolism activity over the posterior anabolism and resulting in a structural deficit.  It has been associated with type 2 diabetes, osteoarthritis, post-myocardial infarction heart failure and several acute and chronic diseases. 
At least one-third of the patients with sudden sensorineural hearing loss had a disrupted blood-labyrinth,  increasing the permeability of the blood vessels in the inner ear and up-regulating the pro-inflammatory cytokines. It has been observed in various damaging conditions, including noise over-stimulation. 
This study aimed to evaluate the possible associations between the genetic polymorphism of IL-1β +3954 (rs1143634) and hearing loss related to a history of occupational noise exposure.
| Methods|| |
Study design and area
This cross-sectional study was approved by the Human Research Ethics Committee at the University of North Paraná (0070/09). It is part of a broader investigation, the "Aging and Longevity Study," which has been conducted in Londrina since 2009. The city of Londrina (approximately 500,000 inhabitants) is situated in the North region of the state of Paraná, Brazil.
From a population of 43,610 elderly people enrolled in the 38 primary care units in the urban area of the city, the sample size was defined at 343 subjects, considering a confidence interval of 95% and an acceptable error margin of 5%.  The sample was a randomly stratified set, considering the gender and the five regions of the city (15% from the central region, 27% from the northern region, 23% from the southern region, 19% from the eastern region, and 16% from the western region). The study included individuals aged 60 years and over, of both genders, who were living independently and classified at level 3 or 4 as proposed by Spirduso.  This classification evaluates the independence level of the elderly, with level 1 indicating a lack of self-mobility and level 5 indicating athletes. Elderly people who had any illness or limitation that would prevent the testing, such as physical or mental disabilities, were excluded from the sample. All the participants signed an informed consent form.
The audiological evaluation was performed in a sound-proof room with an interacoustics audiometer. To determine the hearing loss severity, the means 3000, 4000, and 6000 Hz (mean II) were analyzed and both right and left ears were evaluated. , To analyze the effect of genetic differences on the susceptibility to noise, the cases were classified into two groups: normal (≤25 dB deficit) and hearing loss (>25 dB deficit). 
Occupational exposure to noise assessment
The assessment of occupational exposure to noise was obtained through personal interviews with the elderly participants using a semi-structured questionnaire. Information was collected on working or not in a noisy occupation, years of employment in a noisy job and wearing of a hearing aid. In addition, demographic characteristics (sex, age, and ethnicity) were collected.
Peripheral blood specimens were collected in 6% Ethylenediaminetetraacetic acid vacuum tubes and DNA was extracted using a protocol described by Olerup and Zeterquist. 
From the original samples, the DNA was diluted to a concentration of 100 ηg/μL. The concentration was determined by a 260 nm and a 280 nm spectrophotometer (Biomate 3, Thermo Fischer Scientific, Madison, USA).
Genotype of IL-1β polymorphism
The site C to T polymorphism, located at the + 3954 position in the IL-1β gene (rs1143634), was amplified resulting in a 182 bp fragment. The polymerase chain reaction (PCR) mixture contained 1X PCR buffer, 1.5 μM MgCl 2 , 8 μM each of deoxyribonucleotide triphosphates, 1 μM of each sense and anti-sense primers and two units Taq DNA polymerase (Invitrogen, Carlsbad, CA, USA).
The primers used were: Forward 5′ CTC AGG TGT CCT CGA AAG AAA TCA A 3′ and Reverse 5′ GCT TTT TTG CTG TGA GTC CCG 3′ (Invitrogen, Carlsbad, CA, USA). 
PCR amplification was performed in a thermal cycler (Endurance TC-512 Techne™, Burlington, New Jersey, United States) under the following conditions: Initial denaturation at 95°C for 5 min, followed by 30 cycles at 95°C for 1 min, 67°C for 1 min, and 72°C for 1 min, and a final extension step at 72°C for 5 min.
The PCR product was subject to digestion with five units Taq I (Invitrogen, Carlsbad, CA, USA) overnight at 65°C. Digested fragments were separated on 2% agarose gels (Invitrogen Life Technologies®, São Paulo, Brazil) with 1X tris-Borate-EDTA running buffer. To check the PCR conditions, the sample with known genotype was used and, as a negative control, ultra-pure water was used.
Visualization of amplifications by agarose gel electrophoresis
A 100 bp DNA ladder was included in each gel. The agarose gel was stained with 5 μl of Sybr Safe (Invitrogen Life Technologies®, São Paulo, Brazil) and visualized under UV illumination. The reading and interpretation of the agarose gels were made with the LabImage L-PIX (H.E) 1D-L340 program (Loccus Biotecnologia®, São Paulo, Brazil). The products of 85 bp + 97 bp fragments (allele C), a single 182 bp fragment (allele T) and the three fragments (85 bp, 97 bp + 182 bp) in the presence of both C and T alleles were observed.
The statistical analysis of the data was performed using the SPSS package, version 17.0 (SPSS Inc., Chicago, IL, USA). The genotypes at the + 3954 C/T (rs1143634) locus were grouped as "T+" (TT and CT) and "T-" (CC) carriers. The participants with hearing loss were divided into two groups: With a history of occupational noise exposure and without a history of occupational noise exposure. To compare the distributions of genotypes as well as the frequencies of alleles for + 3954 IL-1β (rs1143634) polymorphism between the groups, the Chi-square test was performed. The Hardy-Weinberg equilibrium was tested in each group, also using the Chi-square test. A P ≤ 0.05 was considered as statistically significant.
| Results|| |
Out of a total of 343 elderly participants, 292 presented hearing loss. Female (59.9%) and Caucasian (62.7%) elderly were predominant. The mean age was 70.6 ± 6.5 years. The prevalence of hearing loss with a history of occupational noise exposure was 33.9% [Table 1].
|Table 1: General characteristics and allele/genotypes frequencies among elderly Brazilians (n=292)|
Click here to view
As shown in [Table 1], 51.0% of the elderly were homozygotes to allele C, 17.2% were homozygotes to allele T and 31.8% were heterozygotes. The C/T allele frequencies were 0.67:0.33, respectively. The distribution of IL-1β alleles was within the Hardy-Weinberg equilibrium (P > 0.05).
There was no significant association between the IL-1β +3954 genotypic frequencies and hearing loss related to a history of occupational noise exposure (χ 2 = 0.538; P = 0.676). Also, no association was observed between the grouped genotypes and hearing loss with or without a history of occupational noise exposure (χ 2 = 0.377; P = 0.621) [Table 2].
|Table 2: Association between the interleukin‑1β +3954 (rs1143634) genotypes frequencies and hearing loss related of history of occupational noise exposure (n=292)|
Click here to view
| Discussion|| |
Noise is harmful starting from 85 dBA and can lead both to mechanical and to metabolic damage of the cochlea. , Fujioka et al.  demonstrated that, in noise-induced damaged cochlea, the inflammation-related cytokines were up-regulated and that the time courses of their expressions were very similar to those seen in other traumatized organs. In noise-induced damaged cochlea, the expression of pro-inflammatory cytokines has not yet been clarified, even though the existence of active inflammatory cells has been reported.  It is well established that, under the same level of noise exposure, the severity of hearing impairment is not the same between different persons. This inter-individual variability might be due to an interaction between genetic, individual and environmental factors. Considering this background, determining the IL-1β gene polymorphism in patients with hearing loss related to a history of noise exposure may help us to understand the individual variability of inflammation in hearing loss.
In the present study, the C and T alleles frequencies were 66.9% and 33.1%, respectively. Others studies have also shown the predominance of the ancestral allele (C), ranging from 60% to 70%. ,, We observed a higher frequency of CC genotype (51.0%), followed by CT (31.8%) and TT (17.2%). This is consistent with the previously cited studies. ,,
Pro-inflammatory cytokines are produced in various organ after tissue damage not only in experimental immune-response models but also in various types of insults, including infection, ischemia, trauma, cryo-ablation and burns,  by various types of cells, including residential immune-related cells (such as leukocytes, macrophages, microglia, and dendritic cells), neurons and glia in the central nervous system.  As disruption of the blood-labyrinth barrier is associated with increased permeability of blood vessels in the inner ear, inflammation may be related to the etiology of these inner ear diseases. 
The studies of Fujioka et al.  and Hirose et al.  pointed out the possibility of inflammatory changes in noise-over-stimulated cochleae. Interestingly, Fujioka et al.  observed the expression and relative induction of IL-1β and TNF-α before IL-6 RNA expression after noise exposure.
Although the mechanism and function of these cytokines in NIHL are still obscure, it is known that the structure and expression of a cytokine can be influenced by genetic variation, resulting in evident pathologic consequences.  The functionality of SNPs with regard to gene expression is an important subject in disease-association studies, and is associated with avoiding disease in late life; their frequency has been shown to differ between younger and older individuals. 
Noise exposure induces the production of IL-1β, IL-6, and TNF-α by the cochlear structure, initiating an inflammatory response and damaging itself.  The higher levels of IL production also upregulates the mucin secretion in the middle ear and contributes to otitis media (middle ear inflammation).  Studies in animals have confirmed the higher expression of the IL-1β genes correlated with hearing loss and tinnitus (perception of sound in the absence of acoustic stimulation); it may affect the N-methyl-D-aspartate receptors, but the exact mechanism is still unclear. 
In the present study, we did not observe an association between the polymorphic genotype of IL-1β (rs1143634) and hearing loss associated with a history of occupational noise exposure. Although the IL-1α gene polymorphism (-889 C/T) has been associated with sudden sensorineural hearing loss and Ménière`s disease,  it is noteworthy that the same study found no association between IL-1β (-511 C/T) gene polymorphism and sudden sensorial hearing loss.
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Regina C Poli-Frederico
Department of Molecular Biology, Centre of Research in Health Sciences, University of Northern Parana (UNOPAR). Paris Avenue 675, Jd. Piza, CEP 86041-140, Londrina, PR
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2]
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