*5.5.2 Estrogen* related receptor *γ* **(***ESRRG***)**

*Esrrg* mRNA has been shown to be expressed at embryonic stages in the mouse cochlear and vestibular ganglion [161], which suggests a role in the inner ear function and development. Moreover, there is considerable evidence supporting an auditory protective effect of estrogen and estrogen-related receptors on the auditory system [162, 163]. In humans, several studies have shown that ARHL is more common and severe with early onset in men as compared to women [164, 165]. For instance, in an analysis of 6134 individuals from three separate European cohorts, an association was found between the minor allele of SNP *rs2818964* and hearing status only in women. Additionally, *Esrrg* knockout mice revealed that at 12 weeks, average hearing thresholds in female mice were 15 dB worse than in males [166].

## **5.6 Genes involved in metabolic pathways**

Studies on human subjects with ARHL have also identified specific polymorphisms in a few genes involved in the folate metabolism pathway. A recent report that genotyped an ARHL cohort from South India revealed several specific polymorphisms within genes encoding thymidylate synthase (*TYMS*) and 5,10-methylenetetrahydrofolate reductase (*MTHFR*). Some polymorphisms such as the *MTHFR* A1298C were noted to protect against the development of ARHL, while others such as *MTHFR* C677T were associated with an increased risk of ARHL in this population [167].
