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

IF 7.9 1区医学 Q1 IMMUNOLOGY

Journal of autoimmunity Pub Date : 2025-04-01 DOI:10.1016/j.jaut.2025.103414

Yuanyuan Yang , Wencong Liu , Zechang Zhang , Yujia zhang , Xuebin Wang , Jing Wang , Huaifang Cai , Yichan Liu , Ran Meng , Yuqi Fu , Hongmin Luo , Lei Yang , Wenxuan Liu

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Abstract

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.

Abstract Image

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探索胰高血糖素样肽-1受体激动剂作为自身免疫性疾病的潜在疾病调节剂

胰高血糖素样肽-1受体（GLP-1R）激动剂正在作为治疗药物出现，用于治疗两种最常见的代谢紊乱：糖尿病和肥胖。然而，GLP-1R激动剂与自身免疫性疾病之间的因果关系尚不清楚。方法利用现有的药物靶基因（GLP-1Rs）顺式等位基因（cis- eqtl）作为GLP-1R激动剂暴露的指标。为确保遗传仪器的可靠性，以肥胖和2型糖尿病（T2DM）为阳性对照。采用孟德尔随机化（MR）来揭示遗传代理GLP-1R激动剂与来自IEU OpenGwas数据库和FinnGen数据库的18种自身免疫性疾病的因果关系。最后，对两个数据库的结果进行meta分析。结果共纳入22个显著的顺式eqtl单核苷酸多态性作为遗传工具。阳性对照分析显示，GLP-1R激动剂与肥胖（OR = 0.826, p = 0.021）和2型糖尿病(OR = 0.886, p <；0.001)，这与meta分析一致。MR分析显示，GLP-1R基因表达增加对1型糖尿病（T1DM）、甲状腺功能减退、原发性胆管炎（PBC）和类风湿性关节炎（RA）具有显著的保护作用。然而，MR分析表明，GLP-1R激动剂的表达增加可能增加Graves病（GD）、溃疡性结肠炎（UC）和牛皮癣的风险。我们的发现与meta分析的结果一致。结论本研究从遗传变异的角度为自身免疫性疾病的潜在辅助治疗提供了新的见解，为GLP-1R激动剂的安全性提供了证据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of autoimmunity 医学-免疫学

CiteScore

27.90

自引率

1.60%

发文量

117

审稿时长

17 days

期刊介绍： The Journal of Autoimmunity serves as the primary publication for research on various facets of autoimmunity. These include topics such as the mechanism of self-recognition, regulation of autoimmune responses, experimental autoimmune diseases, diagnostic tests for autoantibodies, as well as the epidemiology, pathophysiology, and treatment of autoimmune diseases. While the journal covers a wide range of subjects, it emphasizes papers exploring the genetic, molecular biology, and cellular aspects of the field. The Journal of Translational Autoimmunity, on the other hand, is a subsidiary journal of the Journal of Autoimmunity. It focuses specifically on translating scientific discoveries in autoimmunity into clinical applications and practical solutions. By highlighting research that bridges the gap between basic science and clinical practice, the Journal of Translational Autoimmunity aims to advance the understanding and treatment of autoimmune diseases.