Common Fund Data Supplement to A Multivariate Predictive Model for Long- term Disability Post Subarachnoid Hemorrhage in Caucasian and African Populations (NIH/NINR 1R01NR017407)

本申请是作为对NOT-RM-19-009的回应提交的，作为NIH/NINR的补充 1R01NR017407（PI：Stanfill）。动脉瘤性蛛网膜下腔出血（aSAH）相对年轻 这是一个严重的个人问题，死亡率和严重残疾率很高。虽然社会、临床和遗传因素 虽然每一种都被独立地证明与残疾有关，但仍然有很大一部分 与非裔美国人相比， 白人患者R 01提案的目的是为有效干预奠定基础 通过准确识别最有风险的个人和识别导致种族差异的因素， 看到这些人群。在我们强大的试点数据指导下，利用现有的两个 数据库，我们有两个具体的目标：1）使用社会，临床和遗传数据，我们建议开发一个 高加索人队列中aSAH后12个月残疾的预测模型;和2）使用社会、临床和 基因数据，我们建议在非洲人中开发一个aSAH后12个月残疾的预测模型。 美国队将比较这两个模型的一致性，以深入了解驱动 这些群体之间的结果差异。作为母项目的一部分，我们希望找到基因组 我们的候选多巴胺能和多巴胺能通路中的变异对预测残疾有影响 结果。但是，亲本R 01不具有收集基因表达数据的能力，因此不清楚 这些变体如何改变转录，从而改变神经递质活性，以进行药物干预。这 补充提案将通过使用共同基金基因型-组织表达（GTEx）来填补这一空白 数据该数据集允许测量我们选择的用于脑组织中基因表达的SNP， 提供了一个机会来探索大脑环境是如何改变患者与这些遗传变异。 此外，GTEx项目还使我们能够确定血液中是否发生类似的变化， 而这反过来又可以作为大脑表达的替代标记。这些信息可以构成 护理点测试的关键，通过该测试可以进行个性化的药物干预。我们提出了三 补充的具体目的：1）使用来自脑组织样品的GTEx基因型和表达数据，测试GTEx基因的表达。 在我们的候选多巴胺能和多巴胺能神经元中， 2）使用来自血液样品的GTEx基因型和表达数据，测试GTEx基因型和表达之间的关联。 在我们的候选多巴胺能和多巴胺能神经元中， 3）使用GTEx数据来测试大脑和整个大脑之间的基因表达数据的关联性。 血液组织拟议的工作将利用从GTEx项目收集的数据， 全血和脑组织中基因表达的R 01研究。这将产生重大影响， 精确定向的干预措施，以改善aSAH后的结果和生活质量。

This application is being submitted in response to NOT-RM-19-009, as a supplement to NIH/NINR 1R01NR017407 (PI: Stanfill). Aneurysmal subarachnoid hemorrhage (aSAH) strikes relatively young individuals and carries high rates of mortality and severe disability. While social, clinical, and genetic factors have each independently been shown to be associated with disability, there remains a large portion of unexplained variability as well as great disparities in outcome for African American patients as compared to Caucasian patients. The objective of the parent R01 proposal is to lay the foundation for effective intervention by accurately identifying individuals most at risk and identifying the factors contributing to the racial disparities seen for these populations. Guided by our strong pilot data and leveraging the power of two existing databases, we have two specific aims: 1) Using social, clinical, and genetic data, we propose to develop a predictive model for disability 12 months post aSAH in a Caucasian cohort; and 2) Using social, clinical, and genetic data, we propose to develop a predictive model for disability 12 months post aSAH in an African American cohort. The uniformity of the two models will be compared for insights into factors driving the disparities in outcome between these groups. As a part of the parent project, we expect to find genomic variants in our candidate dopaminergic and serotonergic pathways that are influential for prediction of disability outcomes. However, the parent R01 does not have the ability to collect gene expression data, so it is not clear how these variants alter transcription and thus neurotransmitter activity for pharmacologic intervention. This supplemental proposal will fill that gap through the use of Common Fund Genotype-Tissue Expression (GTEx) data. This dataset allows the measurement of our selected SNPs for gene expression in brain tissue, which will give an opportunity to explore how the brain environment is altered in a patient with these genetic variants. Furthermore, the GTEx project also allows us the ability to determine whether similar changes occur in blood, and which in turn could be used as surrogate markers for brain expression. This information could form the crux of a point of care test, by which personalized pharmacologic intervention might occur. We propose three supplemental specific aims: 1) Using GTEx genotype and expression data from brain tissue samples, test the association between SNPs and gene expression for identified SNPs in our candidate dopaminergic and serotonergic pathways; 2) Using GTEx genotype and expression data from blood samples, test the association between SNPs and gene expression for identified SNPs in our candidate dopaminergic and serotonergic pathways; and 3) Use GTEx data to test the association of gene expression data between brain and whole blood tissues. The proposed work will leverage the data collected from the GTEx project to expand the funded R01 study to gene expression in whole blood and brain tissue(s). This will have significant impact by informing precisely targeted interventions to improve outcomes and quality of life post aSAH.