Age-Related Hearing Impairment 1

Description

Age-related hearing impairment (ARHI), or presbycusis, is the progressive bilaterally symmetric deterioration of hearing ability that occurs with aging. Studies of the cochlea in many animal species and of the histopathology of human temporal bones have shown that stria vascularis volumes and spiral ganglion cell, inner hair cell, and outer hair cell populations, as well as many other cochlear cell types and structures, undergo age-related degeneration. Environmental risk factors for ARHI include noise exposure, smoking, ototoxic medication, and cardiovascular disease. Heritability estimates vary between 0.25 and 0.75 depending on, among other factors, study design (family vs twins), age range of the study population, and the phenotype studied (Huyghe et al., 2008).

Mapping

Huyghe et al. (2008) reported the results of a cross-sectional family-based genetic study of ARHI employing audiometric data. By using principal component analysis, they were able to reduce the dimensionality of this multivariant phenotype while capturing most of the variation and retaining biologically important features of the audiograms. Huyghe et al. (2008) studied 1,126 subjects of European descent from 204 large sibships in 9 centers located in 7 European countries. Phenotypic data were available for 955 subjects, 430 men and 525 women with a median age of 61 years (ranging from 49 to 76). Subjects with medical conditions or pathologies that could potentially affect hearing ability were excluded. Air conduction pure-tone hearing thresholds were measured at various kHz. Bone conduction was tested as well. Hearing thresholds were corrected for age, gender, and collection center, and classical principal component analysis was performed on the scaled residuals. Huyghe et al. (2008) conducted a genomewide association as well as linkage scan with high density SNP microarrays. Because of the presence of genetic population substructure, association testing was stratified after which evidence was combined by metaanalysis. No association signals reaching genomewide significance were detected. However, a linkage peak on chromosome 8 was identified with a multipoint lod score of 4.23 at the position of SNP rs4512366 (physical position 125528900; pointwise p value = 5 x 10(-6)), for a principal component related to audiogram shape. This signal reached genomewide significance as assessed by simulations. The region reaching significance on chromosome 8 spanned approximately 7 Mb, roughly between SNPs rs3765212 and rs4601326. This corresponds to cytogenetic chromosome bands 8q24.13-q24.22.

Van Laer et al. (2008) screened SNPs in 70 genes that were candidates for hearing loss in 2,318 patients with age-related hearing impairment derived from 9 centers in 7 European countries. A significant association was found with rs10955255 in intron 1 of the GRHL2 (608576) gene on chromosome 8q22 (p = 8.4 x 10(-5) after Bonferroni correction). Subsequent analysis of this SNP for each center separately showed the same direction of the association, with 2 centers having significant results. Van Laer et al. (2008) noted that a frameshift mutation in the GRHL2 gene (608576.0001) had been associated with an autosomal dominant form of progressive nonsyndromic sensorineural hearing loss (DFNA28; 608641), and suggested that variation in the GRHL2 gene may change gene expression and influence susceptibility to age-related hearing impairment.

Animal Model

The C57BL/6J mouse strain shows a classic pattern of age-related hearing loss by 12 to 15 months of age. Someya et al. (2009) found that mice with deletion in the proapoptotic Bak gene (600516) had significantly less age-related hearing loss compared to wildtype mice. Preservation of hearing was associated with reduced oxidative stress-induced apoptosis of spiral ganglion cells and cochlear hair cells. In vitro studies on primary cochlear cells showed that oxidative stress was associated with overexpression of Bak and apoptosis. Oral supplementation of wildtype mice with the mitochondrial antioxidants alpha-lipoic acid and coenzyme Q10 suppressed Bak expression in the cochlea, reduced cochlear cell death, and prevented age-related hearing loss. Someya et al. (2009) suggested that BAK is required for the development of age-related hearing loss, and that induction of a BAK-dependent mitochondrial apoptosis program in response to oxidative stress is a key pathogenic mechanism.