Causal Associations of Metformin with Five Interleukin Receptors: Uncovering Potential Anti-inflammatory Mechanisms through Mendelian Randomization

Objective This study aims to investigate the causal relationships between metformin (Met) and interleukin (IL) receptors using Mendelian randomization (MR) methods, providi ng new theoretical evidence for the clinical application of Met.

Instrumental variables (IVs) were obtained from genome-wide association study (GWAS) databases. The TwoSampleMR package in R was used to perform MR analysis with the inverse variance weighting (IVW) method. Sensitivity analyses were conducted using the leave-one-out (LOO) method. The Cochran Q test was used to assess heterogeneity, and MR-Egger regression intercept and P values were used to test and correct for horizontal pleiotropy. Publication bias was assessed using funnel plots. Metformin was used as the exposure factor, and two study cohorts were assigned: a training cohort (ID: ukb-b-1 4609) and a testing cohort (ID: ukb-a-159). The outcomes were five IL receptors: IL-6 rec eptor subunit alpha (IL-6 sRa), IL-2 receptor subunit alpha (IL-2 sRa), IL-17 receptor B (IL-17BR), IL-12 receptor subunit beta-2 (IL-12RB2), and IL-1 receptor-like 1 (IL-1RL1).

In the training cohort analysis, all five IL receptors showed significant negative causal relationships with Met (P < 0.05). In the testing cohort analysis, Met had significant negative causal relationships with IL-6 sRa, IL-17BR, IL-12RB2, and IL-1RL1 (P < 0.05). No significant pleiotropy or heterogeneity was detected, and the results were robust.

This study reveals significant negative correlations between Met and the five IL receptors through MR analysis, suggesting that Met may directly or indirectly modulate IL receptors to exert its potential therapeutic effects. This provides new theoretical e vidence for the application of Met in inflammation-related diseases. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study did not receive any funding Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: https://api.opengwas.io/profile/ I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors All data produced in the present work are contained in the manuscript All data produced are available online at:https://api.opengwas.io/profile/