Genetic factors in outcome from traumatic brain injury

描述（由申请人提供）：此提交是对RFA-HD-03，“恢复和康复的遗传基础”的回应。创伤性脑损伤（TBI）是造成死亡和发病的一个主要原因，特别是在45岁以下的人群中。在美国，每年约有55,000人死于创伤性脑损伤，另外每年还有50,000人遭受长期的身心问题，限制了他们的独立性和工作能力。损伤的严重程度、年龄和急性住院期间的并发症等因素只能部分解释结果，遗传因素可能使某些个体在脑外伤后的功能预后较差。人类基因组计划的最新进展已经确定了一些基因的共同多态性，这些基因已被提出调节神经组织对损伤的反应。我们的假设是，多态基因的某些等位基因的遗传可以预测创伤性脑损伤后神经系统恢复不良。证明这一原理的证据是，在几项研究中，一个这样的基因APOE4与成人脑外伤后的不良预后有关。了解哪些基因可能导致脑外伤后的不良结果，可能有助于开发量身定制的治疗方法，以限制损伤或改善功能恢复。该提案有三个具体目标：(1)收集800名受试者的DNA，其中400名儿童和400名成人，他们都是德克萨斯州达拉斯市儿童医疗中心和帕克兰纪念医院的重症监护室收治的TBI患者。结果将在6个月时确定，使用对中度TBI后产生的细微缺陷敏感的结果测量。(2)采用病例对照法，确定APOE4基因的遗传对儿童与成人脑外伤后预后的影响是否存在差异，以及在轻度至中度脑外伤患者中是否存在差异，而在重度脑外伤患者中是否存在差异。(3)对1000个多态候选基因进行大规模的等位基因关联研究，以确定某些多态等位基因的遗传是否与TBI后不良预后相关。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，这些疾病被认为与TBI具有共同的病理生理特征，或者在神经组织对创伤的反应中发挥作用的生物学合理性。这些研究可能为TBI后特定基因在组织反应中的作用提供遗传学证据，并可能为治疗干预确定新的靶点。

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.