Abstract Body (Do not enter title and authors here): Background: Peripheral arterial disease (PAD) is a major cause of morbidity and mortality, particularly in type 2 diabetes mellitus (T2DM). Current treatments for diabetic PAD patients have limited efficacy, necessitating novel therapeutic approaches. The GIPR and GLP1R pathways have emerged as potential targets. This study leverages genetic data from the Million Veteran Program (MVP) to investigate the roles of GIP, GIPR, and GLP1R in PAD pathogenesis.

Methods: We analyzed 51,330 European ancestry PAD cases and 256,807 controls. Locus zoom plots assessed genetic associations at GIP, GIPR, and GLP1R loci. Fine mapping (SuSiE) identified credible SNPs at GIP/GIPR, and Mendelian randomization (MR) evaluated causal effects of glycemic traits (HbA1c, T2DM) on PAD. Colocalization analysis assessed shared genetic signals.

Results: GIP was significantly associated with PAD (rs35895680, P = 1e-10), with fine mapping identifying it as the most likely causal SNP (PIP = 0.993). While GIPR was not genome-wide significant, fine mapping identified an eQTL variant (rs8105523) linked to decreased GIPR expression. Colocalization confirmed shared genetic signals between PAD and HbA1c (PP = 0.99). MR analysis linked decreased GIPR expression with increased PAD risk for HbA1c (OR = 2.88, P = 0.020) and T2DM (OR = 1.95, P = 0.040).

Conclusion: These findings highlight the therapeutic potential of dual GLP1R/GIPR agonists like Tirzepatide in PAD, supporting further clinical trials to validate incretin-based therapies in diabetic PAD patients.