Effect of glucagon-like peptide 1 receptor agonism on exercise blood pressure: genome-wide association and mendelian randomization analyses

Background: An exaggerated systolic blood pressure (SBP) response to exercise increases the risk of cardiovascular morbidity and mortality. Glucagon-like peptide 1 receptor (GLP-1R) agonists are commonly used to treat conditions such as diabetes and obesity and have also been shown to confer numerous cardiovascular benefits. For example, our laboratory has previously shown in a preclinical model of peripheral artery disease (PAD) that GLP-1R agonism reduced the exaggerated SBP response to exercise. To our knowledge, however, there have been no investigations of the potential for GLP-R agonism to reduce the SBP response to exercise in human subjects. Purpose: We performed genetic analyses to investigate the physiological plausibility of using GLP-1R agonism to reduce the SBP response to exercise in human subjects. Methods: We first performed a genome-wide association study (GWAS) in a publicly available database. We then performed Mendelian Randomization (MR) analyses extending on both the GWAS performed herein and publicly available GWAS summary statistics to investigate the effects of GLP-1R agonism on exercise SBP responses, and potential inflammatory-mediating mechanisms. The primary outcome for the GWAS was the SBP response to exercise. In brief, participant genomic data were aligned with the NIH All of Us exome reads to focus on gene-coding regions; the data were filtered to include only biallelic single-nucleotide polymorphisms (SNPs) that had passed the initial All of Us quality control. Linear regression in Hail was used as the statistical model. The regression was adjusted for age, sex, and the first 3 principal components of ancestry. Variants were identified initially at a reduced genome-wide significance of p< 5x10-6, given the limited sample size. Using genetic summary statistics from this GWAS, the association between GLP-1R agonism and exercising SBP was tested with MR. To proxy GLP-1R agonists, SNP genetic variants were extracted from Genotype Tissue Expression (GTEx v6) summary statistics to identify eQTL, or expression quantitative trait loci, which are SNPs that impact the expression of a specific gene. Variants that achieved relaxed threshold criteria (p-value < 5x10-2, r2 < 0.05, clumping window size = 10,000 kb) were selected. Results: 553 participants were included in the GWAS analysis. This cohort was predominantly women (56.6.%), ≥65 years of age (60.2%), and of European descent (85.2%). Four significant variants (rs1419649095, rs111766024, rs1346746193, and a novel variant located at chromosome 14, base position 77024912) were identified, all at a threshold p< 5x10-6. These summary statistics were then used for the primary outcome in MR. 38 SNPs were used to create an instrumental variable genetic proxy for GLP-1R agonism. In weighted median analysis, genetically proxied GLP-1R agonism was associated with a significantly greater SBP response to exercise (β: 31.5 mmHg per allelic fold change, SE: 15.5, p=0.042). Results were supported by sensitivity analysis (p< 0.05). No heterogeneity or horizontal pleiotropy was detected. The instrumental variable to represent the KEAP1-NRF2 pathway included 81 SNPs. The KEAP1-NRF2 pathway mediated 58.5% of the association between GLP-1R agonism and the SBP response to exercise. Conclusion: Our findings provide genetic evidence for a direct causal relationship between GLP-1R agonism and exaggerated SBP responses during exercise. Subsequent mediation analyses revealed a role for oxidative stress in this pathway. Further work is warranted to elucidate PAD-specific genetic mechanisms. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.