Performance of Cardiovascular Polygenic Risk Scores in Carotid Stenosis Identification
Tiffany R Bellomo1,2,3, Anika Misra1, Tianrun Cai4
1Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Insights
Polygenic risk scores for peripheral artery disease (PAD) and coronary artery disease (CAD) show promise in identifying individuals at higher risk for carotid stenosis. These scores may aid in risk stratification beyond traditional factors.
Area of Science:
- Genetics and Cardiovascular Disease
- Atherosclerosis Research
- Precision Medicine
Background:
- Carotid stenosis is a significant risk factor for ischemic stroke, but predicting its progression is challenging.
- Polygenic risk scores (PRSs) for related cardiovascular diseases (CVD) have shown associations with atherosclerosis.
- The utility of PRSs for predicting carotid stenosis is not well-established.
Purpose of the Study:
- To evaluate the association and discriminative performance of PRSs for CAD, PAD, IS, and cIMT with carotid stenosis.
- To determine if PRSs can improve risk prediction for carotid stenosis.
Main Methods:
- Utilized data from the Mass General Brigham Biobank (MGBB) with validated phenotyping for carotid stenosis.
- Employed logistic regression to assess PRS associations, adjusting for age, sex, and ancestry.
- Evaluated incremental discrimination using changes in Harrell's C-statistic.
Main Results:
- PAD, CAD, and IS PRSs were significantly associated with carotid stenosis (p<0.0001), while cIMT PRS was not.
- The PAD PRS showed the greatest improvement in discrimination (ΔC-statistic 0.017).
- Individuals in the top PRS percentiles for PAD and CAD had a 3-fold increased odds of carotid stenosis.
Conclusions:
- PAD and CAD PRSs may help identify individuals at high likelihood for carotid stenosis.
- These PRSs can serve as adjunctive tools for risk stratification, improving upon traditional risk factors.
- Further research into carotid-specific PRSs in diverse populations is warranted for enhanced precision risk assessment.
Background:
Clinically 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).
Methods:
Carotid 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 Harrell's C-statistic.
Results:
Compared 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 (ΔC-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 (ΔC-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.
Conclusions:
A 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.
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