Project Summary Stroke poses a major public health concern as a leading cause of death and disability worldwide. A known cause of ischemic stroke is cervical carotid artery stenosis (CAS), where atherosclerotic plaque can rupture and directly embolize to the brain. Although there exists an efficacious surgical intervention for primary prevention of ischemic stroke secondary to CAS, a critical barrier to progress is the inability to predict which patient populations may benefit from early surgery. This has necessitated a continued search for the etiology of CAS progression. Although genetic studies have been leveraged to better understand similar atherosclerotic diseases, the genetic exploration of CAS has been limited to poorly defined phenotypes and clinically insignificant CAS. This proposal is designed to explore the genetic underpinnings of CAS and stratify high risk patients in need of early surgery. Comparing and contrasting the genetic architecture of patients with asymptomatic and symptomatic CAS will allow identification of novel loci associated with the transition from asymptomatic to symptomatic CAS. Preliminary data shows adequate power for the two genome wide association studies (GWAS) proposed, as diagnoses codes defined symptomatic CAS yields 7,300 patients to compare to healthy controls and asymptomatic CAS yields 10,000 patients to compare to healthy controls (Aim 1b). Given diagnoses codes related to asymptomatic CAS are particularly subject to error, the asymptomatic CAS phenotype will be further improved with additional carotid ultrasound parameters to ensure presence of clinically significant CAS (Aim 1a). The cohorts used, including Massachusetts General Biobank, Penn Medicine Biobank, United Kingdom Biobank, the Million Veterans Program, and AllOfUs, all have available carotid ultrasound information. To further risk stratify patients with CAS for surgery, the previously validated ischemic polygenic risk score (PRS) will be applied to a population of clinically significant CAS and tested for accuracy in selecting patients with symptomatic CAS (Aim 2a). A new multi-ancestry multi-trait PRS will be generated and tested in conjunction with clinical characteristics for improvement in selection of symptomatic CAS (Aim 2b). CAS resulting in stroke is one of many end-point atherosclerotic diseases that can be studied jointly to identify novel pleiotropic genetic architecture common to all diseases. A multi-trait analysis of CAS, peripheral artery disease, coronary artery disease, and ischemic stroke will facilitate discovery of loci that unify atherosclerosis across multiple vascular beds, providing opportunities for prevention and treatment of atherosclerosis (Aim 3). Completion of this proposal will pave the way for tailored therapeutic interventions to prevent CAS progression, generate risk stratification tools for preventative surgery selection, and provide a broader understanding of the progression of atherosclerosis across different vascular beds. Through guidance from skilled mentors, the skills acquired will position the PI well to become an independently funded investigator.

Project Narrative Although there exists an efficacious surgical intervention for primary prevention of stroke resulting from carotid artery stenosis (CAS), a critical barrier to progress is the inability to identify which patients with CAS are going to have a stroke and would benefit from early surgery. Given the genetic exploration of CAS has been limited, this project aims to identify genes responsible for CAS causing stroke, develop a genetic score to stratify high risk patients for surgery, and provide novel opportunities for prevention and treatment of atherosclerosis in general toward reducing the risk of stroke.