Exploring glucagon-like peptide-1 receptor agonists as potential disease-modifying agents in autoimmune diseases.

Background: Glucagon-like peptide-1 receptor (GLP-1R) agonists are emerging with therapeutic agents for the treatment of two of the most prevalent metabolic disorders: diabetes and obesity. However, the causal relationship between GLP-1R agonists and autoimmune diseases is still unclear.

Methods: The available cis-eQTLs for drug target genes (GLP-1Rs) were used as proxies for exposure to GLP-1R agonists. Obesity and type 2 diabetes mellitus (T2DM) were used as positive controls to ensure the reliability of the genetic instrument. Mendelian randomization (MR) was performed to reveal the causal association of genetic proxy GLP-1R agonists with 18 autoimmune diseases from the IEU OpenGwas database and FinnGen database. Finally, the results of the two databases were analyzed via meta-analysis.

Results: A total of 22 significant cis-eQTL single-nucleotide polymorphisms were included as genetic instruments. Positive control analysis revealed that GLP-1R agonists were significantly associated with obesity (OR = 0.826, p = 0.021) and T2DM (OR = 0.886, p < 0.001), which is consistent with the meta-analysis. MR analysis revealed that increased expression of the GLP-1R gene has a significant protective effect on type 1 diabetes mellitus (T1DM), hypothyroidism, primary biliary cholangitis (PBC) and rheumatoid arthritis (RA). However, the MR analysis suggested that increased expression of GLP-1R agonists may increase the risk of Graves' disease (GD), ulcerative colitis (UC) and psoriasis. Our findings were consistent with those of the meta-analysis.

Conclusions: This study provides new insights into potential adjuvant treatments for autoimmune diseases from the perspective of genetic variation and provides evidence for the safety of GLP-1R agonists.