Genetic Markers May Help Predict Amputation Risk in Peripheral Artery Disease

Peripheral artery disease (PAD) is a common condition in which plaque buildup narrows arteries in the legs, arms, and pelvis, and it can progress before symptoms are obvious. In the U.S., an estimated 10–12 million people have PAD, and about 150,000 leg amputations occur each year. Clinicians still cannot predict which patients will face limb-threatening complications. New findings demonstrate that shared genomic traits may help identify PAD patients at heightened risk.

Northeastern University researchers conducted a genome-wide association study (GWAS) to investigate genetic signals linked to lower-extremity amputation in PAD and published the work in the International Journal of Molecular Sciences. The team analyzed thousands of de-identified patient records drawn from the National Institutes of Health (NIH) All of Us Research Program to search for variants associated with severe disease. The investigators indicated that such insights could ultimately support development of tests that estimate amputation risk in patients diagnosed with PAD.

GWAS systematically surveys large DNA datasets to compare the frequency of specific genomic variants in people with a condition versus those without it. According to the description cited by the researchers, the method screens medical databases of patients’ DNA to pinpoint variants that are enriched among individuals with the target phenotype. Applied to PAD, this approach aimed to reveal inherited factors that may predispose certain patients to limb loss.

The analysis identified 38 suggestive genetic variations that the authors associated with a potentially increased chance of progressing to amputation-level disease. The variants mapped to biological functions already linked to vascular health, including the structure of blood vessels and capillaries as well as inflammatory regulation. While the results highlight plausible molecular pathways, the authors emphasized that further testing and verification are needed before any clinical application is considered.

The study was limited to a single dataset from the NIH All of Us Research Program, and the researchers noted that findings have not yet been validated across external cohorts. Planned work includes validating the signals using patient data from the University of California San Diego Health foot and ankle care center, with additional collaborations anticipated with Maine Medical Center and MedStar Georgetown University Hospital.

"This is powerful because you won't have to wait for symptoms. It will allow us to give treatment before the patients start suffering and could basically prevent amputation," said Saeed Amal, research professor of bioengineering at Northeastern University's Roux Institute.

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Northeastern University's Roux Institute