A Functional riboSNitch in the 3′ Untranslated Region of<i>FKBP5</i>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 (<i>FKBP5</i>), a critical regulator of glucocorticoid sensitivity, affect vulnerability to stress-related disorders. In a previous report, <i>FKBP5</i> rs1360780 was identified as a functional variant because of its effect on gene methylation. Here we report evidence for a novel functional <i>FKBP5</i> 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 <i>in silico</i>, <i>in vivo</i>, and <i>in vitro</i> 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 <i>FKBP5</i> expression levels increased as cortisol and glucocorticoid receptor (<i>NR3C1</i>) mRNA levels increased, consistent with increased glucocorticoid resistance. Bioinformatic, <i>in vitro</i>, and mutational analyses indicate that the rs3800373 minor allele reduces the binding of a stress- and pain-associated microRNA, miR-320a, to <i>FKBP5</i> via altering the <i>FKBP5</i> mRNA 3'UTR secondary structure (i.e., is a riboSNitch). This results in relatively greater <i>FKBP5</i> 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 <i>FKBP5</i> mRNA expression may constitute useful therapeutic strategies.<b>SIGNIFICANCE STATEMENT</b><i>FKBP5</i> 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 <i>FKBP5</i> that influences vulnerability to chronic post-traumatic pain in two ethnic cohorts. Using multiple complementary experimental approaches, we show that the <i>FKBP5</i> rs3800373 minor allele alters the secondary structure of <i>FKBP5</i> mRNA, decreasing the binding of a stress- and pain-associated microRNA, miR-320a. This results in relatively greater <i>FKBP5</i> translation, unchecked by miR-320a, increasing glucocorticoid resistance and increasing vulnerability to post-traumatic pain.