Genetic factors in outcome from traumatic brain injury

描述(申请人提供)：本意见书是对RFA-HD-03“康复和康复的遗传基础”的回应。创伤性脑损伤是导致死亡和发病的主要原因，尤其是在45岁以下的人群中。在美国，每年约有5.5万人死于脑外伤，另外每年还有5万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。创伤的严重程度、年龄和急性住院期间的并发症等因素只是影响预后的部分因素，遗传因素很可能使某些人在脑外伤后功能预后较差。人类基因组计划的最新进展已经确定了一些基因的常见多态，这些基因被提出用来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预示着颅脑损伤后神经功能恢复的不良。这一原理的证据是，在几项研究中，有一种名为APOE4的基因与成人脑外伤后预后不良有关。了解哪些基因可能导致颅脑损伤后预后不良，这可能有助于开发定制的治疗方法，以限制损伤或改善功能恢复。这项提案有三个具体目标：(1)收集800名儿童和400名成年人的DNA，这些人在德克萨斯州达拉斯的儿童医学中心和帕克兰纪念医院因脑外伤而住进ICU。结果将在6个月时确定，使用对中度颅脑损伤后产生的细微缺陷敏感的结果衡量标准。(2)采用病例对照的方法，确定APOE4基因遗传对儿童和成人脑损伤后预后的影响是否与成人不同，以及在轻到中度而不是重度脑损伤患者中是否有所不同。(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颅脑损伤后的不良预后相关。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，这些疾病被认为与脑外伤具有共同的病理生理特征，或在神经组织对创伤的反应中发挥作用的生物学可能性。这些研究可能为特定基因在脑外伤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.