Genetic factors in outcome from traumatic brain injury

描述（由申请人提供）：本提交材料是对RFA-HD-03“恢复和康复的遗传基础”的回应。“创伤性脑损伤（TBI）是死亡和发病的主要原因，特别是在45岁以下的人中。在美国，每年约有55，000人死于TBI，每年另有50，000人遭受长期的身体和心理问题，限制了他们的独立性和工作能力。诸如损伤的严重程度、年龄和急性住院期间的并发症等因素仅部分地解释了结果，并且遗传遗传因素可能使某些个体在脑外伤后具有较差的功能结果。人类基因组计划的最新进展已经确定了许多基因中的共同多态性，这些基因被提出来调节神经组织对损伤的反应。我们的假设是，遗传多态性基因的某些等位基因是预测不良的神经功能恢复从TBI。这一原理的证据是，在几项研究中，其中一种基因APOE 4与成人TBI后的不良结局有关。了解哪些基因可能导致TBI后预后不良，可能有助于开发定制治疗以限制损伤或改善功能恢复。该提案有三个具体目标：（1）从800名受试者（400名儿童和400名成人）中收集DNA，这些受试者在德克萨斯州达拉斯的儿童医疗中心和帕克兰纪念医院因TBI而入住ICU。结果将在6个月时确定，使用对中度TBI后导致的细微缺陷敏感的结果测量。(2)为了确定，使用病例对照方法，是否APOE 4的遗传对TBI后的结果的影响在儿童与成人相比不同，以及是否在轻度至中度而不是重度TBI患者中不同。(3)对1,000个多态性候选基因进行大规模等位基因关联研究，以确定某些多态性等位基因的遗传是否与TBI后不良结局相关。这些候选基因的选择是基于它们与其他神经系统疾病的联系，这些神经系统疾病被认为与TBI共享病理生理学特征，或者在神经组织对创伤的反应中起作用的生物可接受性。这些研究可能为特定基因在TBI后组织反应中的作用提供遗传学证据，并可能确定治疗干预的新靶点。

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.