Performance of Cardiovascular Polygenic Risk Scores in Carotid Stenosis Identification

Abstract

BackgroundClinically significant carotid stenosis remains a major cause of ischemic stroke (IS), yet prediction of disease progression is limited. Polygenic risk scores (PRSs) for coronary artery disease (CAD) and peripheral artery disease (PAD) have demonstrated associations with atherosclerosis burden and major cardiovascular disease (CVD) events, but whether these insights extend to carotid stenosis is unclear. We evaluated the association and discriminative performance of validated PRSs for CAD, PAD, IS, and carotid intima-media thickness (cIMT) with carotid stenosis among participants of the Mass General Brigham Biobank (MGBB). MethodsCarotid stenosis was identified in genotyped MGBB participants using validated ICD-and CPT-based phenotyping algorithms. Logistic regression adjusted for age, sex, and 10 ancestry principal components assessed PRS associations. Incremental discrimination was evaluated using changes in Harrells C-statistic. ResultsCompared with 52,636 controls, 670 participants with carotid stenosis were more frequently male (61.5% vs 44.1%), older (70.8 SD 9.0 vs 53.4 SD 17.2 years), and more likely to be European (95.7% vs 84.1%). The IS (OR 1.31, 95% CI 1.21-1.41), CAD (OR 1.62, 95% CI 1.50-1.75), and PAD (OR 1.66, 95% CI 1.54-1.80) PRSs were each associated with carotid stenosis (all p<0.0001), while the cIMT PRS was not (OR 1.04, 95% CI 0.97-1.13; p=0.28). The PAD PRS demonstrated the greatest improvement in discrimination beyond age, sex, and ancestry ({Delta}C-statistic 0.017; C-statistic 0.845, 95% CI 0.833-0.856). A fully adjusted model incorporating established CVD risk factors achieved a C-statistic of 0.852 (95% CI 0.841-0.862), with modest further improvement after PAD PRS inclusion ({Delta}C-statistic 0.008). Individuals in the top 5% of the PAD PRS distribution and top 4% of CAD PRS demonstrated 3-fold greater odds of carotid stenosis. ConclusionsA PAD and CAD PRS may help identify individuals at high likelihood for carotid stenosis, though broad discriminative performance remains limited. These findings support further investigation of CVD PRSs as adjunctive risk stratification tools. Clinical Perspective Whats New?O_LIPolygenic risk scores (PRSs) for peripheral artery disease (PAD), coronary artery disease (CAD), and ischemic stroke (IS), and carotid intima media thickness (cIMT) were each independently associated with carotid stenosis presence. C_LIO_LIThe PAD PRS demonstrated the strongest discrimination for carotid stenosis, whereas the ischemic stroke PRS demonstrated the weakest and the cIMT PRS demonstrated no discriminatory ability. C_LIO_LIBoth the PAD and CAD PRS improved discrimination beyond traditional cardiovascular risk factors and identified carotid stenosis without IS, with IS, and overall, with up to 3-fold greater odds of carotid stenosis. C_LI Clinical ImplicationsO_LIThe PAD and CAD PRS may serve as an adjunctive tool for carotid stenosis identification beyond traditional cardiovascular risk factors. C_LIO_LIDevelopment and validation of carotid-specific PRSs in diverse populations may further improve precision risk assessment for carotid atherosclerotic disease. C_LI