Evaluating the causal effect of using glucagon-like peptide-1 receptor agonists on the risk of autoimmune diseases

Abstract

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.