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

Area of Science:

• Immunology
• Endocrinology
• Genetics

Background:

• Glucagon-like peptide-1 receptor (GLP1R) agonists are increasingly used for type 2 diabetes.
• The potential impact of GLP1R agonists on autoimmune diseases remains unclear.
• Understanding these associations is crucial for patient safety and therapeutic guidance.

Purpose of the Study:

• To investigate the causal association between the use of GLP1R agonists and the risk of developing various autoimmune diseases.
• To explore the potential mechanisms underlying these associations by examining the effect of GLP1R agonists on immune cell phenotypes.

Main Methods:

• Utilized cis-eQTLs for GLP1R as genetic proxies for GLP1R agonist exposure.
• Employed Mendelian randomization (MR) to assess the association with 11 autoimmune diseases, using type 2 diabetes as a positive control.
• Replicated findings in the FinnGen study and performed meta-analysis. Conducted further MR analysis on 731 immune cell phenotypes.

Main Results:

• GLP1R agonists were associated with a reduced risk of hypothyroidism (OR=0.89) but an increased risk of ulcerative colitis (OR=1.48), type 1 diabetes (OR=1.34), systemic lupus erythematosus (OR=1.61), and sarcoidosis (OR=1.38).
• No significant associations were found for asthma, Crohn's disease, multiple sclerosis, or myasthenia gravis.
• GLP1R agonists showed significant associations with 221 positively correlated and 317 negatively correlated immune cell phenotypes.

Conclusions:

• GLP1R agonists exhibit a causal association with several autoimmune diseases.
• The observed associations may be mediated through the modulation of a wide range of immune cell phenotypes.
• These findings highlight the complex interplay between metabolic drugs and immune system regulation.