Genetics of carotid artery disease progression among patients who have failed non-operative management

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.

Grant Number: 5F32HL174327-02
NIH Institute/Center: NIH
Principal Investigator: Tiffany Bellomo