PAD-associated genetic variants are more strongly associated with surgical intervention than premature onset

Peripheral artery disease (PAD) affects over 200 million globally and often progresses without timely diagnosis, necessitating early risk identification. Recent studies have identified 19 PAD-associated single nucleotide polymorphisms (SNPs), but their associations with disease severity have not been fully explored. This study explored the association between these 19 variants and PAD severity using 6,815 PAD patients and 401,872 controls of White European ancestry from the UK Biobank. We classified PAD cases into 4 groups with increasing levels of severity based on age of PAD diagnosis and surgical status. Genetic association analysis for PAD and markers of severity was conducted using REGENIE, and a 19-variant polygenic risk score (PRS) was developed to further evaluate the associations with severity subtypes. The PRS association was then replicated using subjects from an institutional genetic program Generations (N=70 PAD cases, N=2,450 controls). From the association analysis of the 19 variants comparing four severity PAD subtypes with non-PAD controls, two SNPs (rs4722172 and rs505922) showed stronger odds ratios (ORs) with more severe subtypes. For example, the OR of rs4722172 when comparing non-premature surgical PAD with non-PAD controls was 1.08 (95% CI: 1, 1.16) while it increased to 1.18 (95% CI: 1.03, 1.36) for premature surgical PAD. Additionally, eight variants showed greater ORs for surgical compared to non-surgical PAD among premature and non-premature PAD cases respectively. Consistent with single-variant analysis, the 19-variant PRS was significantly higher in surgical groups compared to non-surgical groups (OR=1.14, 95% CI: 1.08, 1.20; p-value=5.85×10 ^-7 ) while no significant difference was identified for non-premature and premature PAD (OR=0.98, 95% CI: 0.9, 1.07, p-value=0.64). This same pattern was observed in the subjects from Generations. Our findings demonstrate that SNPs associated with PAD development may also be associated with PAD severity as assessed by surgical intervention and age of onset (or diagnosis).