Differential effect of panic on the DNA methylation of the glucocorticoid receptor gene exon 1F in chronic subjective tinnitus with distress

Tinnitus can be regarded as a chronic stressor, leading to dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. There is important comorbidity with anxiety, particularly panic, potentially associated with differences in HPA axis functioning and methylation patterns of HPA axis-related genes. This study examines DNA methylation of the glucocorticoid receptor gene (NR3C1) exon 1F in adults with chronic subjective tinnitus and the possible differential effect of panic. METHODS: In a well characterized tinnitus sample (n = 22, half of which had co-occurring panic attacks), and unaffected controls (n = 31) methylation patterns of the CpG sites were determined using pyrosequencing and compared between groups through linear mixed models. Gene expression was determined using quantitative PCR on mRNA. RESULTS: Comparing the combined tinnitus groups to the control group, no DNA methylation differences were observed; however, the tinnitus group with panic attacks showed consistently higher mean methylation values across all CpGs compared to the tinnitus-only and the control group (P = 0.03 following Tukey correction), which became even more pronounced when accounting for childhood trauma (P = 0.012). Moreover, a significant positive correlation was found between methylation of the CpG7 site and the Beck Anxiety Inventory total score (P = 0.001) in the total population. NR3C1-1F expression was not significantly different between the three groups. CONCLUSION: Panic is associated with higher DNA methylation of the NR3C1 exon 1F in adults with chronic subjective tinnitus, consistent with the reduced negative glucocorticoid feedback and HPA axis hyperfunction observed in individuals with panic disorder.