Effects of FKBP5 on Stroke Outcome in Mice and Men: A Translational Study.

Abstract

FKBP5 (FK506-binding protein 51, protein), encoded by the <i>FKBP5</i> (gene, human), is a glucocorticoid receptor-regulating cochaperone. FKBP5 has been suggested as a mediator between stress, vascular morbidity, and neuropsychiatric complications. In this translational proof-of-concept study, we investigated the impact of <i>FKBP5</i> on stroke outcome in mice and men. <i>Fkbp5</i> (gene, mouse) knockout and wild-type mice were subjected to transient brain ischemia. Lesion volume was assessed at 48 hours after stroke using magnetic resonance imaging. Circulating corticosterone level and adrenal gland weight were determined at 72 hours. Observational data from the Prospective Cohort with Incident Stroke Berlin were used to explore associations between <i>FKBP5</i> gene variants and functional outcome after 1 year. Poor functional outcome at 1 year was defined as a modified Rankin Scale score of 0 to 1 versus 2 to 6. Risk allele <i>ACT</i> from a predefined <i>FKBP5</i> haplotype (rs9296158, rs3800373, rs1360780) versus non-<i>ACT</i> was used as the exposure variable. Logistic regression analyses were performed and adjusted for potential confounders. <i>Fkbp5</i> knockout mice showed reduced corticosterone levels and adrenal weights, together with smaller infarct lesions at 48 hours. Four hundred thirty-three patients with available <i>FKBP5</i> haplotype were included in the Berlin stroke cohort. <i>FKBP5</i> risk haplotype <i>ACT</i>, which was present in 204 patients, was associated with poor functional outcome at 1 year (adjusted odds ratio, 1.7 [95% CI, 1.02-2.7]). Loss of <i>Fkbp</i>5 leads to improved outcome in experimental stroke. In addition, the <i>FKBP</i>5 risk haplotype, indicative of increased <i>FKBP5</i> expression, was associated with poor functional outcome following stroke.