FKBP5 variant rs3800373 alters FKBP5 RNA secondary structure and prevents stress-induced miRNA-320a downregulation of FKBP5, resulting in glucocorticoid resistance and increa

Undergraduates: Kyle Riker, Linnstaedt SD, Kutchko KM, Lackey L, AA Site PIs, Laederach A, McLean SA

Faculty Advisor: Sarah Linnstaedt
Department: Chemistry

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Glucocorticoid receptor (GR) co-chaperone FKBP5 minor allele genetic variant rs3800373 predicts worse chronic posttraumatic pain (CPTP), and microRNA-320a directly regulates FKBP5 RNA and predicts CPTP in a stress-dependent manner. In this study we evaluated the hypothesis that rs3800373 alters miR-320a binding._x000D_
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Using a cohort of African Americans presenting to the emergency department after motor vehicle collision, we validated the association between rs3800373 and CPTP (n=907) used total RNA- and microRNA-seq data (n=96 and 172, respectively) to evaluate associations between FKBP5, GR, and miR-320a expression among individuals with and without the minor allele, and evaluated miR-320a/FKBP5 RNA binding in vitro and in vivo. _x000D_
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Individuals with the rs3800373 minor allele experienced greater CPTP. In these individuals, FKBP5 and NR3C1 expression were highly correlated (r=0.67, p=9x10-6), suggesting glucocorticoid resistance, and, unlike those without the minor allele, no negative correlation between miR-320a and FKBP5 RNA was observed, suggesting escape from miR-320a regulation. Allele-specific miR-320a binding was supported by luciferase reporter assays, and in vivo SHAPE data suggested that differences in miR-320a binding are due to allele-specific changes in RNA secondary structure. _x000D_
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The FKBP5 rs3800373 risk variant prevents stress-induced miR-320a downregulation of FKBP5, resulting in glucocorticoid resistance and increased vulnerability to chronic posttraumatic pain._x000D_