Genetic factors in outcome from traumatic brain injury

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DESCRIPTION (provided by applicant): This submission is in response to RFA-HD-03, "Genetic Basis of Recovery and Rehabilitation." Traumatic brain injury (TBI) is a major cause of mortality and morbidity, particularly among persons below the age of 45. In the US, approximately 55,000 deaths each year are attributed to TBI, and an additional 50,000 individuals each year suffer long-term physical and psychological problems that limit their independence and ability to work. Factors such as severity of injury, age, and complications during the acute hospitalization only partly account for outcome, and it is likely that inherited genetic factors predispose certain individuals to have a poor functional outcome after brain trauma. Recent progress in the Human Genome Project has identified common polymorphisms in a number of genes that have been proposed to regulate the response of neural tissue to injury. Our hypothesis is that inheritance of certain alleles of polymorphic genes is predictive of poor neurologic recovery from TBI. Proof of this principle is that one such gene, APOE4, has been linked with poor outcome after TBI in adults in several studies. Understanding which genes may predispose to poor outcome after TBI will likely be useful in developing tailored therapy to limit damage or improve functional recovery. This proposal has three specific aims: (1) To collect DNA from 800 subjects, 400 children and 400 adults, admitted to the ICU with TBI at Children's Medical Center and Parkland Memorial Hospital, both in Dallas, Texas. Outcome will be determined at 6 months, using outcome measures sensitive to subtle deficits that result after moderate TBI. (2) To determine, using a case-control approach, whether the effect of inheritance of APOE4 on outcome after TBI differs in children compared to adults, and whether it differs in patients with mild to moderate rather than severe TBI. (3) To do a largescale allelic association study with 1,000 polymorphic candidate genes to determine whether inheritance of certain polymorphic alleles is associated with poor outcome after TBI. These candidate genes were chosen based on their linkage to other neurologic diseases that are believed to share pathophysiologic features with TBI, or biologic plausibility of a role in the reaction of neural tissue to trauma. These studies may provide genetic evidence for a role of specific genes in tissue response after TBI, and may identify novel targets for therapeutic intervention.