Presbycusis or Age-related hearing loss (ARHL) is one of the most common age-related diseases. Hearing dysfunction caused by this disease is progressive, irreversible, and, symmetrical bilateral in the cochlea of the inner ear. People first have hearing impairment in high frequencies, then they hear sounds more slowly and, then have problems understanding words. This disease is characterized by mild (low-risk), moderate, and severe (high-risk) grades [1–3].
Presbycusis can start at an early age but it usually occurs at 60 years and older. According to the reports of the World Health Organization, about 1.2 billion people are expected by 2025 [3, 4]. To date, no definitive treatment method has been discovered for patients with presbycusis, but there are some ways to prevent or control it at a younger age. However, researchers are trying to find new methods for the definitive treatment of presbycusis, including gene therapy and stem cell therapy [3, 5].
Presbycusis is a multifactorial disorder in which both genetic and non-genetic (environmental) factors are involved. Environmental factors are divided into two categories: external factors such as lifestyle (alcohol consumption and cigarette smoking ), noise, and chemical exposure (industrial chemical toxins) and individual health factors such as age, ototoxic medications (aminoglycoside antibiotics, salicylates), and chronic disease (diabetes, obesity, cardiovascular disease) underlie this disorder [3, 6]. Important mechanisms involved in the pathogenesis of presbycusis include inflammation, apoptosis, mitochondrial dysfunction, and oxidative stress.
The oxidative stress pathway plays a crucial role in the pathogenesis of presbycusis disease. Oxidative stress is a process caused by the high accumulation of reactive oxygen species (ROS) in many tissues and damage to cells. Produced ROS by mitochondria causes damage to mitochondrial components and eventually leads to disruption of mitochondrial function [7]. The body has developed an antioxidant system against ROS to prevent cell disturbance. In this pathway, antioxidant enzymes including N acetyltransferase (NAT) [8], cytochrome P450 (CYP1A1), glutathione s transferase (GST) such as GSTT1, GSTM1, GSTP1 [9], and UCP proteins are involved [8].
NAT2 is an enzyme that is responsible for the elimination and detoxification of exogenous substances by -N-acetylation and -O-acetylation. Genetic changes in the NAT2 gene have led to an alteration in the functional level of isoniazid acetylation. The velocity of the acetyltransferase enzyme reduces in carriers of the mutant alleles which are called slow acetylators. The G590A polymorphism encodes a slow acetylator that slows down the detoxification mechanism and ultimately leads to the accumulation of xenobiotics in the inner ear. The association between 590G > A with presbycusis was reported by Unal et al in the Turkish population at first [10]. Then after, this association was also confirmed in other populations [8, 11].
UCP2 is an important transporter protein that is also involved in the oxidative stress pathway that facilitates the transport of anions and control produced ROS in mitochondria. Genetic variations in this gene lead to an increase in ROS and cell damage in the inner ear. Recent studies have confirmed the association between G-866A polymorphism of the UCP2 gene with obesity [12] and diabetes [13] but there is only one research about this single nucleotide polymorphism (SNP) and presbycusis disease in the Indian population [8].
In this study, we intend to investigate the association between 590G > A single nucleotide polymorphisms of the NAT2 gene and G-866A of the UCP2 gene, which are both important genes in the oxidative stress pathway, with the risk of presbycusis disease in an Iranian population.