Robert Lipsky, Ph.D.
Director, Translational Research
Inova Neurosciences Institute
Inova Health System

Abstract:

A complex system of activated immune cells and cytokines contributes to the inflammatory response after spinal cord injury (SCI).  Specific receptors are the targets of cytokines in these cells. It is known that the alpha 7 nicotinic acetylcholine receptor, α7nAChR, plays a central role in regulating the inflammatory responses. Previous studies showed that pharmacological inhibitors of α7nAChR have a pro-inflammatory effect, increasing circulating cytokine levels such as tumor necrosis factor (TNF).

This translational research project focused on how genetic factors may modify α7nAChR activity, contributing to functional outcome after SCI.  Of particular interest, the expression of α7nAChR in humans is regulated by a genetic polymorphism of the partially duplicated α7nAChR gene, called CHRFAM7A that is highly expressed in peripheral blood cells. In a small cohort of SCI patients and emergency room consented controls, circulating cytokine data were available from before day 7 post injury up to day 22 at follow-up.  Other biomarker and clinical data were available up to 90 days post injury.  Cytokine levels versus time were analyzed based on CHRFAM7A genotype.  Circulating tumor necrosis factor (TNF) levels were significantly higher in individuals carrying the del2bp form of the variant CHRFMA7A gene.  In addition, noradrenergic metabolites were significantly decreased in plasma while pain scores were significantly elevated in SCI patients carrying the del2bp variant relative to non-carriers from 3 weeks post injury up to 90 days following injury.  Taken together, these data suggest that post-acute pro-inflammatory responses modified by CHRFAM7A gene variation may predict poorer clinical outcome in patients following SCI.