Polygenic Risk Score Predicts Peripheral Artery Disease and Major Adverse Limb Events but Offers Modest Incremental Discrimination

Highlights

– A validated polygenic risk score (PRS) for peripheral artery disease (PAD) was associated with higher odds of prevalent PAD and a higher incidence of major adverse limb events (MALE) in 68,816 patients from six TIMI trials.

– Per 1 standard deviation (SD) increase in the PAD PRS: adjusted odds ratio (OR) for prevalent PAD 1.15 (95% CI 1.12–1.18) and adjusted hazard ratio (HR) for MALE 1.30 (95% CI 1.19–1.42).

– Adding the PAD PRS to established clinical risk factors produced a statistically significant but small improvement in discrimination (AUC 0.651 → 0.662).

Background

Peripheral artery disease (PAD) affects millions worldwide, is underdiagnosed, and carries high risks of limb loss and cardiovascular morbidity and mortality. Traditional risk factors for PAD—age, smoking, diabetes, hypertension, and dyslipidaemia—explain a substantial portion of risk but not all interindividual variability. Genome-wide association studies (GWAS) have identified common variants associated with PAD, enabling development of polygenic risk scores (PRS) that aggregate small effects across the genome to stratify lifetime susceptibility.

Interest in PRS has surged because they can be measured before disease onset and theoretically enable earlier risk stratification and targeted prevention. However, the incremental predictive and clinical utility of PRS for PAD—particularly for hard limb outcomes such as acute limb ischemia, chronic limb-threatening ischemia, major amputation, or peripheral revascularization (together termed MALE)—remains uncertain.

Study design and population

The analysis pooled individual-level genetic and clinical data from six TIMI (Thrombolysis In Myocardial Infarction) clinical trials, focusing on patients with established cardiometabolic disease. The cohort comprised 68,816 participants with a median follow-up of 2.6 years. At baseline 5,986 (8.7%) had known PAD. The investigators applied a recently validated PAD PRS and evaluated its association with prevalent PAD and incidence of MALE during follow-up.

Outcomes: Prevalent PAD at baseline and incident MALE, defined as acute limb ischemia, chronic limb-threatening ischemia, major amputation, or peripheral revascularization. Analyses adjusted for standard clinical covariates (age, sex, smoking, diabetes, hypertension, lipids, and other relevant factors).

Key findings

Sample and event counts: 68,816 participants; 5,986 with baseline PAD (8.7%); 577 MALE events during follow-up.

Association with prevalent PAD

Each 1-SD higher PAD PRS was independently associated with greater odds of prevalent PAD (adjusted OR per 1-SD 1.15; 95% CI 1.12–1.18; P < .0001). The magnitude of this genetic effect was reported to be comparable to that of established clinical risk factors.

Association with incident MALE

Each 1-SD higher PAD PRS was associated with a 30% higher risk of MALE during follow-up (adjusted HR per 1-SD 1.30; 95% CI 1.19–1.42; P < .0001). This relationship persisted after adjustment for traditional clinical risk factors, suggesting the PRS captures information not fully represented by clinical covariates.

Predictive performance and incremental value

Discrimination measured by area under the receiver operating characteristic curve (AUC) increased from 0.651 with clinical risk factors alone to 0.662 after adding the PAD PRS (P < .0001). Although statistically significant in this large sample, the absolute improvement in AUC was modest, raising questions about clinical impact and cost-effectiveness for routine use.

Sensitivity and secondary analyses

The published abstract focuses on the main adjusted estimates; full-text publication likely details subgroup analyses (e.g., by age, diabetes, smoking, ancestry) and metrics such as calibration, net reclassification improvement (NRI), or decision-curve analysis. These metrics are important to judge whether a small AUC gain translates into meaningful clinical decisions.

Expert commentary

Interpretation: The study provides robust evidence that a multi-variant PAD PRS is independently associated with both prevalent PAD and future MALE in a large high-risk cardiometabolic trial population. The HR of 1.30 per SD for MALE is clinically meaningful in relative terms. However, the modest absolute discrimination improvement highlights key limitations of current PRS applications.

Strengths

– Large pooled sample with individual-level genetic and adjudicated clinical outcomes from randomized-trial cohorts.

– Use of a recently validated PRS and rigorous covariate adjustment.

– Focus on clinically important limb outcomes (MALE), not just subclinical disease.

Limitations and caveats

– Population and generalizability: TIMI trial participants are patients with cardiometabolic disease who may differ from community-based populations. Applicability to primary prevention cohorts or to populations with different ancestry distributions requires assessment.

– Ancestral diversity and PRS transferability: Most GWAS and PRS have been derived from European-ancestry datasets; performance attenuates in non-European groups. The manuscript should report ancestry-specific analyses and calibration.

– Event count and follow-up: Although overall sample size is large, only 577 MALE events occurred and median follow-up was 2.6 years—relatively short for atherosclerotic outcomes that accumulate over longer intervals. Longer follow-up would better define cumulative risk and clinical utility.

– Incremental clinical utility: The small AUC gain may not justify routine PRS testing unless it meaningfully changes management (e.g., earlier imaging, intensified preventive therapy) and improves outcomes. Decision-curve analysis, cost-effectiveness, and prospective trials are needed to demonstrate benefit from PRS-informed care.

Biological plausibility and potential mechanisms

GWAS loci for PAD implicate pathways relevant to atherosclerosis, thrombosis, inflammation, and vascular remodeling. A PRS aggregates these small effect genetic variants and likely reflects lifelong susceptibility to peripheral atherosclerosis and impaired vascular repair, pathways distinct but overlapping with coronary artery disease PRS.

Clinical implications and potential use cases

While routine use of PAD PRS is premature, potential applications include:

• Identifying individuals at elevated lifetime risk who might merit earlier ankle-brachial index (ABI) screening or structured vascular assessment.
• Risk stratification among patients undergoing peripheral revascularization to tailor surveillance intensity.
• Enrichment strategies for clinical trials of PAD prevention or limb-salvage therapies.

Before adoption, it will be essential to show that PRS-guided strategies change management in ways that reduce MALE or improve patient-centered outcomes.

Conclusion and future directions

This pooled analysis indicates that a PAD polygenic risk score is independently associated with both prevalent PAD and incident major adverse limb events beyond standard clinical risk factors. The PRS effect sizes are meaningful on a relative scale, but the addition of the PRS to clinical predictors produced only modest improvement in discrimination.

Key next steps include validation in diverse, community-based cohorts; assessment of calibration and clinical net benefit; integration with ABI and imaging; prospective evaluation of PRS-informed interventions; and careful consideration of equity, access, and ethical implications of genomic risk stratification.

Funding and clinicaltrials.gov

The analysis pooled data from six TIMI trials. Funding sources and trial registration identifiers are those reported in the primary TIMI trial publications and the article by Al Said et al. (2025). Readers should consult the primary publication for detailed funding statements and trial registry numbers.

References

1. Al Said S, Patel SM, Melloni GEM, Kamanu FK, Giugliano RP, Wiviott SD, Scirica BM, O’Donoghue ML, Cannon CP, Bhatt DL, Antman EM, Braunwald E, Ellinor PT, Bonaca MP, Sabatine MS, Marston NA, Ruff CT. A polygenic risk score for peripheral artery disease and major adverse limb events. Eur Heart J. 2025 Nov 28:ehaf891. doi: 10.1093/eurheartj/ehaf891. Epub ahead of print. PMID: 41312852.

2. Khera AV, Chaffin M, Aragam KG, et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nature Genetics. 2018;50(9):1219-1224. doi:10.1038/s41588-018-0183-z.

3. Torkamani A, Wineinger NE, Topol EJ. The personal and clinical utility of polygenic risk scores. Nature Reviews Genetics. 2018;19(9):581-590. doi:10.1038/s41576-018-0018-x.

Author note

This article summarizes and interprets the findings of Al Said et al. (2025) for clinicians and policy-makers. It emphasizes methodological context, potential clinical applications, and research gaps. For clinical decision-making, clinicians should consult the full published paper and current guideline statements.