Polygenic Risk Score Flags Silent PAD Threats Before Symptoms Appear: Study Suggests

PAD is a chronic condition in which narrowed arteries reduce blood flow to the limbs, often resulting in pain, reduced mobility, and, in severe cases, amputation. Although environmental and lifestyle factors are well-known contributors, genetics also plays a significant role in determining risk. In this context, researchers designed a new polygenic risk score (PRS-PAD) that incorporates genetic data from multiple ancestries and tested its predictive ability in three large cohorts: the UK Biobank, All of Us Research Program (AoU), and the Mass General Brigham Biobank (MGBB).

The study revealed the following findings:

• The study analyzed data from over 650,000 individuals with detailed genetic and clinical information.
• In the UK Biobank cohort, each standard deviation increase in PRS-PAD was linked to a 63% higher risk of developing peripheral artery disease (PAD).
• Even after accounting for common risk factors like smoking, diabetes, and kidney disease, individuals in the top 20% of PRS-PAD had a significantly greater risk of developing PAD.
• Nearly one-third of PAD cases without traditional risk factors (e.g., smoking, diabetes) had a high PRS-PAD, highlighting its potential to identify hidden risks.
• PRS-PAD was as effective as traditional markers like diabetes and smoking in predicting new PAD cases, with a C statistic of 0.761.
• Among individuals already diagnosed with PAD, a high PRS-PAD was linked to a higher risk of major adverse limb events, such as amputation and acute limb ischemia.
• This increased risk of severe limb events was observed consistently across all three study cohorts, with hazard ratios between 1.56 and 1.75.

While the results point to the clinical value of including genetic screening in PAD management, the authors emphasize the need for further research, particularly to improve the performance of PRS in non-European populations and evaluate its long-term impact on patient care.

"The study opens new doors for integrating genetic data into PAD screening and risk assessment. With continued refinement, polygenic risk scores may help identify high-risk individuals early and guide personalized strategies to prevent severe limb complications," the authors concluded.

Reference:

Flores AM, Ruan Y, Misra A, et al. Polygenic Prediction of Peripheral Artery Disease and Major Adverse Limb Events. JAMA Cardiol. Published online May 21, 2025. doi:10.1001/jamacardio.2025.1182