CRHBP polymorphisms predict chronic pain development following motor vehicle collision

Pain. 2016 Jan;157(1):273-279. doi: 10.1097/j.pain.0000000000000374.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Accidents, Traffic*
  • Adult
  • Alleles
  • Carrier Proteins / genetics*
  • Chronic Pain / etiology*
  • Chronic Pain / genetics
  • Female
  • Gene Frequency
  • Gene-Environment Interaction
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Musculoskeletal Pain / etiology*
  • Musculoskeletal Pain / genetics
  • Polymorphism, Single Nucleotide
  • Receptors, Corticotropin-Releasing Hormone / genetics
  • Receptors, Glucocorticoid / genetics
  • Tacrolimus Binding Proteins / genetics
  • Young Adult


  • Carrier Proteins
  • NR3C1 protein, human
  • Receptors, Corticotropin-Releasing Hormone
  • Receptors, Glucocorticoid
  • corticotropin releasing factor-binding protein
  • CRF receptor type 1
  • Tacrolimus Binding Proteins
  • tacrolimus binding protein 5