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. 2025 Aug 1;10(8):770-778.
doi: 10.1001/jamacardio.2025.1182.

Polygenic Prediction of Peripheral Artery Disease and Major Adverse Limb Events

Alyssa M Flores  1   2   3   4 , Yunfeng Ruan  2   3 , Anika Misra  2   3 , So Mi Jemma Cho  2   3   4 , Margaret S Selvaraj  2   3 , Tiffany R Bellomo  1   2   3   4 , Tetsushi Nakao  2   3   4 , Kenneth Rosenfield  4   5   6 , Matthew Eagleton  1   5 , Whitney Hornsby  2   3 , Aniruddh P Patel  2   3   4   5   6 , Pradeep Natarajan  2   3   4   5   6   7
Affiliations

Polygenic Prediction of Peripheral Artery Disease and Major Adverse Limb Events

Alyssa M Flores et al. JAMA Cardiol. .

Erratum in

  • Error in Results.
    [No authors listed] [No authors listed] JAMA Cardiol. 2025 Aug 1;10(8):864. doi: 10.1001/jamacardio.2025.2648. JAMA Cardiol. 2025. PMID: 40802275 Free PMC article. No abstract available.

Abstract

Importance: Peripheral artery disease (PAD) is a heritable atherosclerotic condition associated with functional decline and high risk for limb loss. With growing knowledge of the genetic basis for PAD and related risk factors, there is potential opportunity to identify individuals at high risk using polygenic risk scores (PRSs).

Objective: To develop a novel integrated, multiancestry polygenic score for PAD (PRS-PAD) and evaluate its risk estimation for PAD and major adverse limb events in 3 populations.

Design, setting, and participants: This longitudinal cohort study was conducted among individuals with genotyping and electronic health record data in the UK Biobank (2006-2021), All of Us (AoU, 2018-2022), and the Mass General Brigham Biobank (MGBB, 2010-2023). Data were analyzed from July 2023 to February 2025.

Exposures: PRS-PAD, previously published PAD polygenic scores, and clinical risk factors.

Main outcomes and measures: The primary outcomes were PAD and major adverse limb events, defined as a surrogate of major amputation and acute limb ischemia.

Results: The study populations included 400 533 individuals from the UK Biobank (median [IQR] age, 58.2 [45.0-71.4] years; 216 215 female participants [53.9%]), 218 500 from AoU (median [IQR] age, 53.6 [37.7-65.0] years; 132 647 female participants [60.7%]), and 32 982 from MGBB (median [IQR] age, 56.0 [32.0-80.0] years; 18 277 female participants [55.4%]). In the UK Biobank validation cohort, PRS-PAD was associated with an odds ratio [OR] per SD increase of 1.63 (95% CI, 1.60-1.68; P < .001). After adjusting for clinical risk factors, the OR for the top 20% of PRS-PAD was 1.68 (95% CI, 1.62-1.74; P < .001) compared to the remainder of the population. Among PAD cases without a history of diabetes, smoking, or chronic kidney disease (n = 3645), 1097 individuals (30.1%) had a high PRS-PAD (top 20%). In incident disease analysis, PRS-PAD improved discrimination (C statistic, 0.761), which was nearly equivalent to the performances of diabetes (C statistic, 0.760) and smoking (C statistic, 0.765). Among individuals with prevalent PAD, high PRS-PAD was associated with an increased risk of incident major adverse limb events in the UK Biobank (hazard ratio [HR], 1.75; 95% CI, 1.18-2.57; P = .005), MGBB (HR, 1.56; 95% CI, 1.06-2.30; P = .02), and AoU (HR, 1.57; 95% CI, 1.06-2.33; P = .03).

Conclusions and relevance: This cohort study develops a new PRS that stratifies risk of PAD and adverse limb outcomes. Incorporating polygenic risk into PAD care warrants further investigation to guide screening and tailor management to prevent major adverse limb events.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Patel reported grants from the US National Heart, Lung, and Blood Institute during the conduct of the study. Dr Natarajan reported grants from Amgen, Apple, Boston Scientific, Genentech/Roche, Allelica, and Novartis; personal fees from Allelica, Apple, AstraZeneca, Bain Capital, Blackstone Life Sciences, Bristol Myers Squibb, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly, Esperion Therapeutics, Foresite Capital, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, Merck, Novartis, Novo Nordisk, TenSixteen Bio, and Tourmaline Bio; holding equity in Bolt, Candela, Mercury, MyOme, Parameter Health, Preciseli, and TenSixteen Bio; and spousal employment by Vertex Pharmaceuticals outside the submitted work. No other disclosures were reported.

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