Genetic Variation related to Glucose Metabolism Modifies Clinical Trajectories of Stroke Survivors

• Applicant: Dr. Shufan Huo
• Subject Area: Human Genetics ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 514143076

Type 2 Diabetes mellitus (T2D) is an important risk factor for stroke and significantly modifies its long-term outcome, increasing the risk of recurrent stroke and post-stroke dementia/death. Genetic significantly contributes to the risk of T2D (estimated heritability 50%). Although polygenic susceptibility to diabetes (PSD), modeled by polygenic risk scores (PRS), strongly correlates with Hemoglobin A1c (HbA1c) levels and increased stroke risk/severity, knowledge on the role of PSD in stroke survivors is lacking. Large studies with available genetic data now allow us to study the contribution of genetically-determined changes in glucose metabolism to poor clinical trajectories in stroke survivors. Aim 1. Evaluate whether higher PSD increases the risk of recurrent stroke, myocardial infarction, T2D and uncontrolled T2D in stroke survivors. Using genetic data on 22,918 stroke survivors enrolled in the UK Biobank and the All of Us (AoU) Research Program, the primary analysis will evaluate whether higher PSD increases the composite risk of recurrent stroke and myocardial infarction. Secondary analyses will investigate the risks of T2D and uncontrolled T2D. We will work with genetic data on 462 independent T2D risk variants, using PRS, Mendelian Randomization analyses and pathway analyses. We will use machine learning to integrate genomic with transcriptomic, proteomic and clinical data to generate precision medicine tools aimed at identifying patients who could benefit from tailored clinical interventions. Aim 2. Evaluate whether these associations vary considering underrepresented groups. Previous work showed significant differences for the burden of stroke between racial and other minorities. Stroke disparities with respect to genetic predisposition to risk factors are not well described in these minorities. AoU provides health data on groups traditionally underrepresented in research. Aim 3. Real-life deployment of a genomic-based precision medicine tool to identify stroke survivors with elevated PSD. We are currently enrolling stroke survivors in Generations, Yale’s signature genomic-based precision medicine program. Leveraging the available genome-wide sequencing data, we will return risk profile information related to PSD to treating clinicians. We will evaluate the proportion of patients who complete the entire process, whether genetic information is appropriately interpreted by clinicians, and whether a higher PSD is associated with elevated HbA1c and uncontrolled T2D. Furthermore, we will investigate the interpretability of returning information on PSD for treating clinicians. Impact This proposal will enhance our understanding of the role of PSD in stroke survivors. We will complete a proof-of-concept implementation of a genomic-based precision medicine strategy to identify stroke survivors with high PSD in a real-life clinical setting. By publicly sharing our resources, we will maximize transparency and accelerate research in these topics

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Dr. Guido Falcone