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.
The parent project and this supplemental application are relevant to public health, as they will promote a better understanding of the relative influences social, clinical, and genetic factors have on disability after aneurysmal subarachnoid hemorrhage (aSAH) and will also give insight into the disparities for this outcome seen between Caucasian and African American patients. This current supplemental proposal will expand the previously funded R01 by adding genotype and gene expression data from brain tissues and blood held in the Common Fund Genotype-Tissue Expression (GTEx) dataset. This work, and the supplemental work, together forms the foundation for a long-term program of research in developing targeted interventions to reduce post-stroke disability and improve outcomes, which will foster the arrival of Precision Medicine for this group.
