A Functional riboSNitch in the 3' Untranslated Region of Alters MicroRNA-320a Binding Efficiency and Mediates Vulnerability to Chronic Post-Traumatic Pain.

Previous studies have shown that common variants of the gene coding for FK506-binding protein 51 (), a critical regulator of glucocorticoid sensitivity, affect vulnerability to stress-related disorders. In a previous report, rs1360780 was identified as a functional variant because of its effect on gene methylation. Here we report evidence for a novel functional allele, rs3800373. This study assessed the association between rs3800373 and post-traumatic chronic pain in 1607 women and men from two ethnically diverse human cohorts. The molecular mechanism through which rs3800373 affects adverse outcomes was established via , , and analyses. The rs3800373 minor allele predicted worse adverse outcomes after trauma exposure, such that individuals with the minor (risk) allele developed more severe post-traumatic chronic musculoskeletal pain. Among these individuals, peritraumatic circulating expression levels increased as cortisol and glucocorticoid receptor () mRNA levels increased, consistent with increased glucocorticoid resistance. Bioinformatic, , and mutational analyses indicate that the rs3800373 minor allele reduces the binding of a stress- and pain-associated microRNA, miR-320a, to via altering the mRNA 3'UTR secondary structure (i.e., is a riboSNitch). This results in relatively greater translation, unchecked by miR-320a. Overall, these results identify an important gene-miRNA interaction influencing chronic pain risk in vulnerable individuals and suggest that exogenous methods to achieve targeted reduction in poststress mRNA expression may constitute useful therapeutic strategies. is a critical regulator of the stress response. Previous studies have shown that dysregulation of the expression of this gene plays a role in the pathogenesis of chronic pain development as well as a number of comorbid neuropsychiatric disorders. In the current study, we identified a functional allele (rs3800373) in the 3'UTR of that influences vulnerability to chronic post-traumatic pain in two ethnic cohorts. Using multiple complementary experimental approaches, we show that the rs3800373 minor allele alters the secondary structure of mRNA, decreasing the binding of a stress- and pain-associated microRNA, miR-320a. This results in relatively greater translation, unchecked by miR-320a, increasing glucocorticoid resistance and increasing vulnerability to post-traumatic pain.