OBJECTIVE: To investigate the causal association of using glucagon-like peptide-1 receptor (GLP1R) agonists with autoimmune diseases.
METHODS: The available cis-eQTLs for drugs target genes (GLP1R) were used as genetic variants for exposure to GLP1R agonists. Type 2 diabetes was used as positive control. Mendelian randomizations (MR) were performed to explore the association of genetically-proxied GLP1R agonists with 11 autoimmune diseases from large-scale consortia. Replicating the findings in the FinnGen study and then pooled with meta-analysis. Finally, we performed MR analysis to examine whether GLP1R agonists affect 731 immune cell phenotypes to clarify the potential mechanism.
RESULTS: We observed supportive evidence to support the association of GLP1R agonists with reduced the risk of hypothyroidism (OR [95 %] = 0.89 [0.82-0.95], P < 0.001), but increased risk of ulcerative colitis (OR [95 %] = 1.48 [1.27-1.71], P < 0.001), type 1 diabetes (OR [95 %] = 1.34 [1.21-1.50], P < 0.001), systemic lupus erythematosus (OR [95 %] = 1.61 [1.29-2.02], P < 0.001) and sarcoidosis (OR [95 %] = 1.38 [1.08-1.75], P = 0.008). There was no supporting evidence to verify the association of GLP1R expression with asthma, Crohn's disease, multiple sclerosis and myasthenia gravis (P > 0.05). In addition, we found that GLP1R agonists was positively associated with 221 immune cell phenotypes (P < 0.05, OR > 1), and negatively associated with 317 immune cell phenotypes (P < 0.05, OR < 1).
CONCLUSION: GLP1R agonists are causally associated with various autoimmune diseases potentially through the modulation of 731 immune cell phenotypes.
