Mendelian Randomization Analysis of the Inflammatory Factor CXCL5 and Type 2 Diabetes Mellitus

Introduction: This study focused on investigating the causal relationship between inflammatory factors and Type 2 Diabetes Mellitus (T2DM) and identifying metabolites associated with inflammatory factors as potential mediators. Methods: Mendelian Randomization (MR) analysis was conducted using pooled genome-wide association study data to genetically predict T2DM. The study was registered under the identifier ebi-a-GCST90018926 and included 38,841 cases and 451,248 controls. In addition, the MR approach was applied to evaluate the effects of metabolite-mediated inflammatory factors on T2DM. Results: MR analysis showed that increased expression of C-X-C motif Chemokine Ligand 5 (CXCL5) was associated with reduced levels of the metabolite 1-linoleoyl-GPE (18:2) (p = 0.0154, 95% Confidence Interval [CI]=0.907, ranging from 0.838 to 0.981). Furthermore, decreased levels of 1-linoleoyl-GPE (18:2) were associated with increased T2DM risk (p = 0.0066, 95% CI=0.957, ranging from 0.926 to 0.988), whereas elevated CXCL5 levels increased the risk of T2DM (p = 0.0041, 95% CI = 1.052, ranging from 1.016 to 1.089). The findings indicated that CXCL5 increased the incidence of T2DM by 8.6% through modulation of 1-linoleoyl-GPE (18:2) levels. Discussion: This study identified a causal relationship between the chemokine CXCL5 and T2DM. The progression of T2DM may be promoted through 1-linoleoyl-GPE (18:2), which acts as a mediator of CXCL5-related effects. Future investigations should further examine the interactions among inflammatory factors, metabolites, and T2DM. Conclusion: Increased expression of the inflammatory factor CXCL5 reduced the level of 1-linoleoyl- GPE (18:2) and promoted the development of T2DM. These findings may help clarify the relationship between inflammatory factors and metabolic diseases.