May 3, 2023Open Access

Cardiovascular Disease Risk Assessment Using Traditional Risk Factors and Polygenic Risk Scores in the Million Veteran Program

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Atherosclerotic cardiovascular disease (ASCVD) (n=79151). Intervention: Polygenic risk scores (PRSs) for CAD and ischemic stroke vs. Traditional clinical risk factors. Primary outcome: Composite ASCVD events (per SD increment of combined PRS in non-Hispanic White participants) (HR 1.20, 95% CI 1.16-1.24).

JVJason L. VassyBoston Medical Center DPDaniel PosnerVA Boston Healthcare System YHYuk‐Lam HoVA Boston Healthcare System

Key Result

Adding polygenic risk scores to traditional risk factors provided modest net reclassification improvement for composite cardiovascular disease, including a 6.79% improvement among women in the intermediate risk group.

Study Design

Type

Cohort (n=79,151)

Multicenter

Yes

Structured PICO

Does the addition of genome-wide polygenic risk scores for CAD and ischemic stroke to traditional risk factors improve ASCVD risk estimation in an ancestrally diverse midlife population?

Population

79,151 adults free of ASCVD and statin naive at baseline from the US Million Veteran Program, mean age 57.8 years, 86.5% male, ancestrally diverse (23.4% non-Hispanic Black, 8.6% Hispanic, 68.0% non-Hispanic White).

Intervention

Genome-wide polygenic risk scores (PRSs) for coronary artery disease (CAD) and acute ischemic stroke added to traditional risk estimation.

Comparator

Traditional clinical risk factors alone (age, sex, systolic blood pressure, total cholesterol, HDL cholesterol, smoking, and diabetes status).

Outcome

Incident nonfatal myocardial infarction (MI), ischemic stroke, ASCVD death, and composite ASCVD events.composite

Adding polygenic risk scores to traditional risk factors provides modest improvement in ASCVD risk discrimination, with greater magnitude of benefit seen in women and younger individuals.

Main Result

Effect estimate: HR 1.20 (95% CI 1.16-1.24)

Limitations

PRSs used were developed in predominantly European ancestry populations and were not multiancestry or transancestry scores
Due to limited follow-up in the MVP, only 5-year ASCVD risk was estimated instead of the usual 10-year risk
High rate of statin use at baseline and large number of participants with clinical CAD who may have undergone revascularization procedures without experiencing a qualifying outcome
Demographic composition was predominantly male, making results potentially less generalizable to women

Abstract

Importance: Primary prevention of atherosclerotic cardiovascular disease (ASCVD) relies on risk stratification. Genome-wide polygenic risk scores (PRSs) are proposed to improve ASCVD risk estimation. Objective: To determine whether genome-wide PRSs for coronary artery disease (CAD) and acute ischemic stroke improve ASCVD risk estimation with traditional clinical risk factors in an ancestrally diverse midlife population. Design, Setting, and Participants: This was a prognostic analysis of incident events in a retrospectively defined longitudinal cohort conducted from January 1, 2011, to December 31, 2018. Included in the study were adults free of ASCVD and statin naive at baseline from the Million Veteran Program (MVP), a mega biobank with genetic, survey, and electronic health record data from a large US health care system. Data were analyzed from March 15, 2021, to January 5, 2023. Exposures: PRSs for CAD and ischemic stroke derived from cohorts of largely European descent and risk factors, including age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, smoking, and diabetes status. Main Outcomes and Measures: Incident nonfatal myocardial infarction (MI), ischemic stroke, ASCVD death, and composite ASCVD events. Results: A total of 79 151 participants (mean SD age, 57.8 13.7 years; 68 503 male 86.5%) were included in the study. The cohort included participants from the following harmonized genetic ancestry and race and ethnicity categories: 18 505 non-Hispanic Black (23.4%), 6785 Hispanic (8.6%), and 53 861 non-Hispanic White (68.0%) with a median (5th-95th percentile) follow-up of 4.3 (0.7-6.9) years. From 2011 to 2018, 3186 MIs (4.0%), 1933 ischemic strokes (2.4%), 867 ASCVD deaths (1.1%), and 5485 composite ASCVD events (6.9%) were observed. CAD PRS was associated with incident MI in non-Hispanic Black (hazard ratio HR, 1.10; 95% CI, 1.02-1.19), Hispanic (HR, 1.26; 95% CI, 1.09-1.46), and non-Hispanic White (HR, 1.23; 95% CI, 1.18-1.29) participants. Stroke PRS was associated with incident stroke in non-Hispanic White participants (HR, 1.15; 95% CI, 1.08-1.21). A combined CAD plus stroke PRS was associated with ASCVD deaths among non-Hispanic Black (HR, 1.19; 95% CI, 1.03-1.17) and non-Hispanic (HR, 1.11; 95% CI, 1.03-1.21) participants. The combined PRS was also associated with composite ASCVD across all ancestry groups but greater among non-Hispanic White (HR, 1.20; 95% CI, 1.16-1.24) than non-Hispanic Black (HR, 1.11; 95% CI, 1.05-1.17) and Hispanic (HR, 1.12; 95% CI, 1.00-1.25) participants. Net reclassification improvement from adding PRS to a traditional risk model was modest for the intermediate risk group for composite CVD among men (5-year risk >3.75%, 0.38%; 95% CI, 0.07%-0.68%), among women, (6.79%; 95% CI, 3.01%-10.58%), for age older than 55 years (0.25%; 95% CI, 0.03%-0.47%), and for ages 40 to 55 years (1.61%; 95% CI, -0.07% to 3.30%). Conclusions and Relevance: Study results suggest that PRSs derived predominantly in European samples were statistically significantly associated with ASCVD in the multiancestry midlife and older-age MVP cohort. Overall, modest improvement in discrimination metrics were observed with addition of PRSs to traditional risk factors with greater magnitude in women and younger age groups.

Ask AI

Helpful

Bookmark

View Full Paper

Ask AI

Helpful

Bookmark

View Full Paper

Cite This Study

Vassy et al. (Wed,) conducted a cohort in Atherosclerotic cardiovascular disease (ASCVD) (n=79,151). Polygenic risk scores (PRSs) for CAD and ischemic stroke vs. Traditional clinical risk factors was evaluated on Composite ASCVD events (per SD increment of combined PRS in non-Hispanic White participants) (HR 1.20, 95% CI 1.16-1.24). Adding polygenic risk scores to traditional risk factors provided modest net reclassification improvement for composite cardiovascular disease, including a 6.79% improvement among women in the intermediate risk group.

synapsesocial.com/papers/6a11e4a571528255b221bd54 https://doi.org/https://doi.org/10.1001/jamacardio.2023.0857

Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: