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. 2013 Aug;154(8):1419-26.
doi: 10.1016/j.pain.2013.04.037. Epub 2013 Apr 26.

Polymorphisms in the Glucocorticoid Receptor Co-Chaperone FKBP5 Predict Persistent Musculoskeletal Pain After Traumatic Stress Exposure

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Free PMC article

Polymorphisms in the Glucocorticoid Receptor Co-Chaperone FKBP5 Predict Persistent Musculoskeletal Pain After Traumatic Stress Exposure

Andrey V Bortsov et al. Pain. .
Free PMC article

Abstract

Individual vulnerability factors influencing the function of the hypothalamic-pituitary-adrenal 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 6 weeks after 2 common trauma exposures. The study included data from 2 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 6 weeks after trauma exposure were assessed using a 0-10 numeric rating scale. After adjustment for multiple comparisons, 6 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 6 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 posttraumatic pain, and that such pathways may be a target of pharmacologic interventions aimed at improving recovery after trauma.

Conflict of interest statement

Conflict of interest: Dr. Diatchenko is a co-founder and equity stock holder in Algynomics, Inc. Other authors declare no conflict of interest.

Figures

Figure 1
Figure 1. FKBP5 haplotypes
FKBP5 haplotypes were estimated from the six SNP genotypes (rs3800373, rs7753746, rs9380526, rs9394314, rs2817032, and rs2817040) predicting overall pain and neck pain six weeks after trauma exposure in the motor vehicle collision cohort. Haplotype frequencies are estimated using the expectation-maximization algorithm. Only haplotypes with a frequency > 0.05 are shown (79% of all haplotypes). Risk alleles of the replicated SNPs are underlined. Rs9380526 was most significantly associated with overall pain intensity and neck pain at week 6 after motor vehicle collision in the motor vehicle collision cohort. Rs2817032 showed the strongest association with overall pain at week 6 after sexual assault. Rs3800373 has been previously reported in the literature to predict PTSD [6]. The results show that all risk alleles belong to two haplotypes (h2 and h3) with combined frequency 0.18.
Figure 2
Figure 2. Overall musculoskeletal pain trajectories and neck pain trajectories
Overall musculoskeletal pain trajectories and neck pain trajectories by rs2817032 genotype in the motor vehicle collision cohort (A, B) and sexual assault cohort (C, D). A), B) After motor vehicle collision, the presence of one or more copies of the C allele was associated acute neck pain in emergency department (ED) (p < 0.05) and with overall and neck pain at six weeks (p < 0.01). Effect of the genotype on pain intensity varied by the time of assessment (assessment time × genotype interaction term p < 0.05). In the sexual assault cohort, the presence of one or more copies of the C allele was associated with overall pain during the month prior to assault (p < 0.01) and with overall pain (p < 0.001) and neck pain (p < 0.01) at six weeks. *p <0.05; **p <0.01; ***p <0.001.

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