Collections > UNC Chapel Hill Undergraduate Honors Theses Collection > A genetic variant associated with post-MVC pain determines the extent of miR-34a binding to ADRA2A

Adrenergic alpha 2A receptors (ADRA2A) are known to play an important role in descending pain pathways and in the generation of stress-induced analgesia. However, the influence of ADRA2A genetic variants on acute pain severity after motor vehicle collision (MVC) has not been assessed. In this study we hypothesized that a genetic variant in the 3’UTR of ADRA2A, rs3750625, would be associated with acute pain outcomes following MVC. In addition, based on bioinformatics analyses, we hypothesized that the allele at this location determines the efficiency of binding of miR- 34a, a microRNA (miRNA) known to regulate pain and stress responses. The association between rs3750625 allele and acute post-MVC pain outcomes was assessed using a study of 948 European Americans who presented to the emergency department (ED) for evaluation after MVC. The rs3750625 genotype was determined from patient blood ED samples using the Sequenom platform. miRNA binding was assessed using a luciferase reporter assay consisting of a miR-34a expression cassette and individual ADRA2A 3’UTR-luc reporters with either the minor or major allele. In regression models adjusted for age, sex, and study site, the minor allele (A) of rs3750625 (n =91/942, 9.7%) was associated with greater ED pain severity (38.3 vs. 26.1), p=0.002). Luciferase reporter assays demonstrated that miR-34a binds the 3’UTR of ADRA2A and that the amount of knockdown is significantly more efficient when the minor allele is present. Additionally, knocking down miR-34a levels in neuroblastoma cells results in increased ADRA2A mRNA and protein expression. These results suggest that genetic variant rs3750625 in the 3’UTR of ADRA2A affects individual vulnerability to acute pain after traumatic events such as MVC, and that this influence may be mediated by miRNA binding.