title: CRHBP polymorphisms predict chronic pain development following motor vehicle collision.
abstract: Musculoskeletal pain (MSP) is a common sequela of traumatic stress exposure. While biological factors contributing to chronic MSP after motor vehicle collision (MVC) have traditionally focused on tissue injury, increasing evidence suggests that neuro/stress/immune processes mediated by stress system activation may play a more dominant role. In a previous study, we found that genetic variants in the hypothalamic-pituitary-adrenal (HPA) axis-related gene FKBP5 influence vulnerability to persistent MSP 6 weeks after MVC. In the present cohort study (n = 855), we evaluated whether genetic variants in several other important HPA axis-related genes, including the glucocorticoid receptor (NR3C1), corticotropin-releasing hormone receptor R1 (CRHR1), and corticotropin-releasing hormone-binding protein (CRHBP), influence risk of chronic MSP over time after MVC. Genetic polymorphism rs7718461 in the CRHBP gene showed significant association (P = 0.0012) with overall pain severity during the year after MVC in regression models controlling for multiple comparisons. Two additional CRHBP alleles in high linkage disequilibrium with rs7718461 also showed trend-level significance. In secondary analyses, a significant interaction between this CRHBP locus (minor allele frequency = 0.33) and time was observed (P = 0.015), with increasing effect observed over time following trauma. A significant CRHBP × FKBP5 interaction was also observed, with substantially increased MSP after MVC in those with a risk allele in both genes compared with either gene alone. The results of this study indicate that genetic variants in 2 different HPA axis genes predict chronic MSP severity following MVC and support the hypothesis that the HPA axis is involved in chronic post-MVC MSP pathogenesis.
authors.affiliation: TRYUMPH Research Program, University of North Carolina, Chapel Hill, NC, USA Anesthesiology, University of North Carolina, Chapel Hill, NC, USA Emergency Medicine, William Beaumont Hospital, Royal Oak, MI, USA Emergency Medicine, Massachusetts General Hospital, Boston, MA, USA Emergency Medicine, Spectrum Health System, Grand Rapids, MI, USA Emergency Medicine, Baystate Medical Center, Springfield, MA, USA Emergency Medicine, North Shore University Hospital, Manhasset, NY, USA Emergency Medicine, Saint Joseph Mercy Health System, Ypsilanti, MI, USA Emergency Medicine, University of Florida College of Medicine, Jacksonville, FL, USA Emergency Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Sarah D
authors.initials: SD
authors.lastname: Linnstaedt
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Bortsov
authors.forename: April C
authors.initials: AC
authors.lastname: Soward
authors.forename: Robert
authors.initials: R
authors.lastname: Swor
authors.forename: David A
authors.initials: DA
authors.lastname: Peak
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Jones
authors.forename: Niels
authors.initials: N
authors.lastname: Rathlev
authors.forename: David C
authors.initials: DC
authors.lastname: Lee
authors.forename: Robert
authors.initials: R
authors.lastname: Domeier
authors.forename: Phyllis L
authors.initials: PL
authors.lastname: Hendry
authors.forename: Samuel A
authors.initials: SA
authors.lastname: McLean
mesh_terms: D000063:Accidents, Traffic; D000328:Adult; D000483:Alleles; D002352:Carrier Proteins / Q000235:genetics*; D059350:Chronic Pain / Q000209:etiology* / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D059352:Musculoskeletal Pain / Q000209:etiology* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics; D022021:Tacrolimus Binding Proteins / Q000235:genetics; D055815:Young Adult; D000099052:CRF Receptor, Type 1; D000099159:Tacrolimus Binding Protein 5
chemical_list: D002352:Carrier Proteins; D018019:Receptors, Corticotropin-Releasing Hormone; D011965:Receptors, Glucocorticoid; D022021:Tacrolimus Binding Proteins; D000099052:CRF Receptor, Type 1; D000099159:Tacrolimus Binding Protein 5; C497713:NR3C1 protein, human; C067133:corticotropin releasing factor-binding protein