Genetic factors in outcome from traumatic brain injury

本文件是对RFA-HD-03“恢复和康复的遗传基础”的回应。“创伤性 脑损伤（TBI）是死亡率和发病率的主要原因，特别是在年龄小于 45.在美国，每年约有55，000人死于TBI，另有50，000人死于TBI。 每年都有许多人遭受长期的身体和心理问题，这些问题限制了他们的独立性， 劳动能力受伤严重程度、年龄、急性住院期间的并发症等因素 只是部分原因，而且很可能是遗传因素使某些人倾向于 脑外伤后的功能预后很差人类基因组计划的最新进展 确定了一些基因中的常见多态性，这些基因被认为是调节反应的基因 神经组织的损伤。我们的假设是，遗传的某些等位基因的多态性基因， 这预示着创伤性脑损伤后神经功能恢复不良。这一原理的证据是，其中一个这样的基因，APOE 4， 在几项研究中，TBI与成人TBI后的不良结局有关。了解哪些基因可能 TBI后易患不良结局的患者可能有助于开发定制治疗以限制损伤或 改善功能恢复。这项建议有三个具体目标：（1）收集800名受试者的DNA， 400名儿童和400名成人，因TBI入住儿童医疗中心和帕克兰的ICU 纪念医院，都在德克萨斯州的达拉斯。将在6个月时使用结局确定结局 对中度TBI后产生的细微缺陷敏感的措施。(2)为了确定，使用病例对照 方法，APOE 4遗传对TBI后结果的影响是否在儿童中与TBI后结果不同， 成年人，以及它是否在轻度至中度而不是重度TBI患者中存在差异。(3)做一个大的- 用1,000个多态性候选基因进行等位基因关联研究，以确定是否遗传 某些多态性等位基因与TBI后的不良结果相关。这些候选基因被选中 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或在神经组织对创伤的反应中起作用的生物相容性。这些研究可以提供 遗传学证据表明特定基因在TBI后组织反应中的作用，并可能确定新的靶点， 治疗干预

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 large- scale 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.