Hearing impairment (HI) is a frequent clinical problem in humans and affected individuals experience deterioration in their communication skills. Since the beginning of the 90s, tremendous progress has been achieved in the understanding of the genetic causes of hereditary HI. This progress, however, is mainly limited to rare, monogenic forms of HI. The etiology of relative frequent forms, such as noise-induced hearing loss (NIHL), is more complex. Up to now, little research has been performed on the genetic factors responsible for these complex forms. NIHL is the second most common form of sensorineural HI, after presbyacusis. Remarkably, the individual susceptibility to NIHL varies greatly. This inter-individual variability is due to an interaction of susceptibility genes and environmental factors. At the moment, a few environmental factors are known to cause a raised susceptibility, including exposure to organic solvents and heavy metals. Laboratory studies have shown that a synergistic effect exists between noise exposure and exposure to chemicals. Furthermore, some studies have demonstrated that individual factors such as smoking, elevated blood pressure, and cholesterol levels may influence the degree of NIHL. In contrast to environmental factors, nothing is currently known about the genetic basis of NIHL. The purpose of this project is to identify genes that cause a raised susceptibility to NIHL. Prof. Dr. Mariola Sliwinska-Kowalska will be responsible for data and DNA sample collection. Within the framework of the NOPHER and NOISECHEM projects, she possesses an extensive database with information concerning the audiometric status, noise exposure, and exposure to chemicals, from 1500 Polish workers. Since the development of NIHL is related to gender, a distinction is made between male and female workers and afterwards individuals are categorized into 3 age groups (<35y, 35-50y, ³51y). Within each age group, individuals are divided into 3 exposure groups (<85dB, 85-91dB, ³92dB). Subsequently, hearing thresholds at the most relevant frequenies (4 and 6 kHz) are evaluated, and for each of the possible subgroups individuals are selected at the two extremes of the phenotypic spectrum viz. 10% most susceptible and 10% most resistant subjects. The selection of patients at the two extremes of the phenotypic spectrum has the advantage of providing a much higher power for the identification of the underlying genes and it reduces the number of samples to be analyzed. To identify the genetic risk factors, an association study will be performed by Single-Nucleotide Polymorphism (SNP) genotyping. SNPs are DNA sequence variations that involve a single nucleotide in the human genome. SNPs have been proposed as efficient tools for the analysis of complex diseases. If a certain SNP allele confers susceptibility to NIHL, it is expected that this SNP allele is more frequent among susceptible individuals compared to resistant individuals. The disease-associated allele may be the direct cause of the disease or it may be in linkage disequilibrium with the disease-causing mutation. As association analysis of the total genome by SNP genotyping would lead to unrealistically high number of SNP analyses, even with efficient high throughput screening methods, we will limit the analysis to SNPs located in candidate genes. Excellent candidates for susceptibility to NIHL are all known genes responsible for monogenic HI, which are also natural candidates for the involvement in complex forms of HI. Genes that protect against oxidative stress and mitochondrial genes can also be considered as important candidates since it is well known that oxidative stress plays a substantial role in the development of NIHL. In addition, a possible association between NIHL and glutathione S-transferase µ, an enzyme with an important anti-oxidative function, has already been described by Rabinowitz et al. (Hearing Res. 2002; 173: 164-171).