The Role of 9p21 Variants and CTSH in Diabetes-Related Risk Factors and the Progression of Peripheral Artery Disease Across Populations

Peripheral artery disease (PAD) is a progressive artery condition that affects more than 200 million people worldwide. It is also one of the leading causes of limb ischemia, amputation, and cardiovascular suffering. The presence of diabetes, especially type 2 diabetes (T2D), accelerates the condition’s progression through inflammation, chronic hyperglycemia, and impaired tissue repair. In recent years, genetic research has identified genetics as an important part of PAD risk. Using a literature search strategy to find 20 peer-reviewed studies across Google Scholar and PubMed/MEDLINE, this review explores the roles of genetic variations, especially in the 9p21 chromosome and the CTSH gene (15q24 chromosome) in the development and progression of PAD, with emphasis on diabetes-related mechanisms and population-specific differences. Variants within the 9p21 region include rs1333049 and rs10811661, which influence vascular cell proliferation, inflammation, and plaque formation in the arteries while interacting with poor glycemic control to increase vascular risk. On the other hand, the CTSH gene contributes to plaque stability, linking vascular disease and diabetes. This review also evaluates how the frequency and impact of these genetic variants differ across populations, showing important trends in PAD susceptibility and clinical outcomes that remain underrepresented in current genetic research. Collectively, the evidence suggests that interactions among genetic susceptibility, diabetes, and other factors shape PAD severity and progression. Having a better understanding of these relationships may support earlier risk stratification, more personalized prevention strategies, and the development of targeted therapies.