(PC214) Genomic Insights into Incretin-Based Therapeutics for Peripheral Arterial Disease

Objectives: Peripheral arterial disease (PAD) is a significant cause of morbidity and mortality, particularly in individuals with type 2 diabetes mellitus (T2DM). Current treatment options for diabetic PAD patients have limited efficacy, underscoring the need for innovative approaches that address underlying pathogenesis. The glucagon-like peptide-1 receptor (GLP1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) pathways have emerged as potential therapeutic targets for PAD. This study utilizes genetic data from the Million Veteran Program (MVP) to investigate the roles of GIP, GIPR, and GLP1R in PAD pathogenesis.

Methods: This study analyzed 51,330 European ancestry PAD cases and 256,807 controls. Genetic associations at GIP, GIPR, and GLP1R loci were assessed using locus zoom plots. Fine mapping was conducted to identify credible SNPs at the GIP and GIPR loci using SuSiE, and Mendelian randomization (MR) was performed to evaluate causal effects of glycemic traits, such as hemoglobin A1c (HbA1c) and T2DM, on PAD. Colocalization analysis assessed shared genetic signals between PAD and glycemic traits.

Results: GIP was significantly associated with PAD (rs35895680, P = 1e-15), with fine mapping identifying this variant as the most likely causal SNP (posterior inclusion probability [PIP] = 0.993; Bayes Factor [BF] = 135.24). While GIPR did not reach genome-wide significance, fine mapping identified two eQTL variants, rs4802263 (PIP = 0.999, BF = 952.05, risk allele = A) and rs8105523 (PIP = 0.988, BF = 78.44, risk allele = G), associated with decreased GIPR expression. Colocalization analysis revealed shared genetic signals between PAD and HbA1c at the GIP locus (posterior probability [PP] = 0.99) and moderate evidence at the GIPR locus (PP = 0.74). MR analysis demonstrated that decreased GIPR expression is causally associated with increased PAD risk for HbA1c (OR = 2.88, 95% CI: [1.10, 7.57], P = 0.020) and T2DM (OR = 1.95, 95% CI: [1.01, 3.49], P = 0.040).

Conclusions: These findings highlight the genetic evidence supporting the potential role of incretin-based therapies, particularly dual GLP1R and GIPR agonists like Tirzepatide, in PAD. Dual agonists may address vascular dysfunction by enhancing both GLP1R and GIPR activity, thus mitigating PAD progression in diabetic populations. However, further clinical trials are needed to validate these therapeutic strategies. This study underscores the translational potential of genomic insights into incretin signaling pathways, offering a foundation for future precision medicine approaches in PAD management.