In clinical practice it is common to see different functional outcomes in individuals with similar degrees of traumatic brain injury (TBI) and comparable pre-injury intellectual, educational, and functional capabilities. Similarly, individual responses to medications can vary enormously. These differences suggest that environmental and other host factors play important roles in outcome. Host genotype might be one such factor. Our knowledge of the role of genetic factors in response to trauma and recovery from trauma, including reactivity to drugs, is in its infancy. However some important preliminary findings are emerging.(for example see 1, 2) This article focuses on candidate polymorphic alleles in genes modulating central dopaminergic function to illustrate some of the underlying principles and prospects for the future.
An array of genetic responses is triggered by neurotrauma both acutely and over time. (3, 4) Polymorphisms in genes responding to neurotrauma, and genes modulating cognition-associated neurotransmitter systems may influence the acute response to trauma as well as adaptation to injury-induced constraints and response to medications used to promote recovery. Polymorphisms that under normal conditions confer no advantage or disadvantage to the host, may, under conditions of injury or decreased reserve, come to play important roles as mediators of outcome.
As a starting point, it is useful to consider four broad categories in which genes could play an important role in outcome after trauma: these include modulation of 1) injury extent, 2) recovery from injury, 3) pre-injury cognitive capacities and reserve, and 4) response to treatment. Each of these four broad categories involves multiple processes and thus is under complex polygenic control. An important characteristic of polygenic traits is that the effect of individual alleles might be subtle but may be additive or interactive with other alleles. Additional power to detect genetic influences on outcome measures can be gained, therefore, by considering an ensemble of candidate alleles that may interact together to produce the trait (e.g. memory impairment or “poor recovery”) (see 5 for full discussion).(5) Many of the genes participating in these four broad domains have not been identified, much less sequenced nor functional polymorphic alleles identified. However, important nodal points in each of these major phases have been defined and several tantalizing candidate genes with interesting functional polymorphisms have been discovered.