GLP-1R expression and dermatological diseases: a mendelian randomization and real-world study.

چکیده اصلی

BACKGROUND: Although glucagon-like peptide-1 receptor (GLP-1R) is widely expressed in multiple tissues and organs including skin and subcutaneous tissue, with diverse physiological roles in metabolism and immunity, the potential causal association between GLP-1R expression and dermatological diseases remains unclear. METHODS: Available cis-expression quantitative trait loci (cis-eQTLs) were selected as genetic instruments for GLP-1R expression. A two-sample Mendelian randomization (MR) analysis was employed to assess the potential causal association between GLP-1R expression and dermatological diseases. Subsequently, a two-step mediation MR analysis was conducted to explore the mediators between GLP-1R expression and dermatological diseases. Finally, a real-world pharmacovigilance analysis using the Food and Drug Administration Adverse Event Reporting System (FAERS) database was conducted to provide supplementary real-world evidence. RESULTS: Our study revealed distinct associations between GLP-1R expression and dermatological diseases. Specifically, GLP-1R expression was significantly associated with a reduced risk of bullous pemphigoid (OR = 0.47, 95% CI = 0.31-0.72, P < 0.001), as well as an increased risk of psoriasis (OR = 1.19, 95% CI = 1.08-1.32, P < 0.001) and urticaria (OR = 1.41, 95% CI = 1.23-1.61, P < 0.001). Further mediation MR analysis suggested that the immune cell phenotype HLA-DR on B cells might mediate the causal association between GLP-1R expression and bullous pemphigoid, with an estimated mediation proportion of 35.7% (P = 0.003). Other immune cells including Monocytic Myeloid-Derived Suppressor Cells Absolute Count, HLA-DR on CD14 + CD16- monocytes, and HLA-DR on CD14 + monocytes were also identified as potential mediators, with estimated mediation proportions of 23.6% (P = 0.010), 13% (P = 0.024), and 12.7% (P = 0.036), respectively. In the complementary FAERS analysis, consistently, GLP-1RAs reports showed a lower reporting signal for bullous pemphigoid than sodium-glucose cotransporter 2 inhibitors (SGLT2is) reports. CONCLUSION: Our findings suggest that GLP-1R expression is associated with a reduced risk of bullous pemphigoid, which may be partly mediated by specific immune cell phenotypes.

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