Polymorphisms in the glucocorticoid receptor co-chaperone FKBP5 predict persistent musculoskeletal pain after traumatic stress exposure

Abstract

Individual vulnerability factors influencing the function of the hypothalamic-pituitary-adrenal (HPA) axis may contribute to the risk of the development of persistent musculoskeletal pain after traumatic stress exposure. The objective of the study was to evaluate the association between polymorphisms in the gene encoding FK506 binding protein 51, FKBP5, a glucocorticoid receptor co-chaperone, and musculoskeletal pain severity six weeks after two common trauma exposures. The study included data from two prospective emergency department-based cohorts: a discovery cohort (n=949) of European Americans experiencing motor vehicle collision and a replication cohort of adult European American women experiencing sexual assault (n=53). DNA was collected from trauma survivors at the time of initial assessment. Overall pain and neck pain six weeks after trauma exposure were assessed using a 0–10 numeric rating scale. After adjustment for multiple comparisons, six FKBP5 polymorphisms showed significant association (minimum p <0.0001) with both overall and neck pain in the discovery cohort. The association of rs3800373, rs9380526, rs9394314, rs2817032, and rs2817040 with neck pain and/or overall pain six weeks after trauma was replicated in the sexual assault cohort, showing the same direction of the effect in each case. The results of this study indicate that genetic variants in FKBP5 influence the severity of musculoskeletal pain symptoms experienced during the weeks after motor vehicle collision and sexual assault. These results suggest that glucocorticoid pathways influence the development of persistent post-traumatic pain, and that such pathways may be a target of pharmacologic interventions aimed at improving recovery after trauma.

Association between <b><i>FKBP5</i></b> Functional Polymorphisms and Completed Suicide

“…Two SNPs have been reported to be associated with increased FKBP5 protein expression and a higher induction of FKBP5 messenger RNA (mRNA) by cortisol in healthy individuals (rs1360780 and rs3800373) [16,17]. The minor T allele of the SNP rs1360780 and the minor C allele of the SNP rs3800373 both located within the intron region of chromosome 6 have been correlated with higher FKBP5 induction by cortisol and reduced GR sensitivity compared with the major allele [15,17,18]. …”

No man is an island: Living in a disadvantaged neighborhood influences chronic pain development after motor vehicle collision

“…In addition, we also hypothesized that this effect is due in part to the influence of low nSES on stress system function, and therefore that living in a disadvantaged neighborhood environment would have a particularly deleterious effect on pain outcomes among those with stress system-related genetic vulnerability factors. We hypothesized that this is because lower nSES has been shown to cause alterations in stress system function [43; 50] (e.g., dysregulated cortisol levels [15; 28]) and because increasing evidence indicates that stress systems are involved in the pathogenesis of persistent MSP after traumatic events such as MVC [2; 6; 40]. To test this hypothesis, we investigated common genetic variation in the locus of the gene coding for co-chaperone FK506 binding protein 51 ( FKBP5 ), because this protein is known to influence hypothalamic-pituitary adrenal (HPA) axis function [48; 59] (an important component of the stress response system), and because FKBP5 variants have been shown to predict persistent neck and overall pain severity after MVC [6].…”

An Integrated Model of Chronic Whiplash-Associated Disorder

“…Genetic diatheses in this context could include a growing list of polymorphisms that affect tissue health, stress reactivity, immune and inflammatory function, and vulnerability to new-onset psychopathology that continue to be identified, recognized, and defined. 8,9,61,62,68,69 As examples directly relevant to this model, catechol-O-methyltransferase, an enzyme responsible for cataboliz- The position that some people are more genetically vulnerable to pain and distress from trauma is new and potentially dangerous for insurance consumers, so we do not wish to prematurely endorse such findings as fact, as causation has yet to be firmly established. While genetics has been introduced into our model, it is with a strong caveat that considerable work remains to be done to establish its role and effects.…”

“…The unfavorable pathway in our model starts with a dysregulated or maladaptive stress response. The mechanisms of such may be genetic, 9,69 or may be related to conditioning through prior life experience. 123 Recent work has revealed that a perception of being the victim of injustice 102,103 or anger management/expression style 12,16 is associated with the experience and/or expression of pain and disability that can be included at this stage.…”