Abstract
OBJECTIVE: Studies have demonstrated a link between chronic inflammatory responses and diabetic microangiopathy, which include diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy. However, it remains unclear whether there is a causal association between circulating inflammatory cytokines and the development of diabetic microvascular complications. This study aimed to investigate whether altered genetically predicted concentrations of circulating inflammatory cytokines were associated with the development of diabetic microvascular complications using two-sample Mendelian randomization (MR) analysis and clinical validation. METHODS: Pooled data on diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and 91 circulating inflammatory cytokines were obtained from publicly available databases. The analysis was conducted mainly using the inverse variance weighting (IVW) method and the results were assessed based on the odds ratio (OR) and 95% confidence interval (CI). In addition, the stability and reliability of the results were verified using the leave-one-out method, heterogeneity tests, and horizontal pleiotropy. Finally, ELISA and RT-qPCR were utilized to assess the expression of relevant inflammatory cytokines associated with diabetic microvascular complications. RESULTS: Mendelian randomization analysis identified a total of 9 circulating inflammatory cytokines that exhibit causal associations with the diabetic microangiopathy, with IL-20RA being a common risk factor for all three conditions. Clinical studies have found elevated plasma IL-20RA concentrations in patients with diabetic peripheral neuropathy, and RT-qPCR testing of peripheral blood mononuclear cells revealed significantly higher IL-20RA mRNA expression in patients with diabetic peripheral neuropathy as compared to normal individuals. CONCLUSION: This study highlights the potential role of specific inflammatory cytokines in the development of diabetic microangiopathy (diabetic nephropathy, diabetic retinopathy and diabetic neuropathy). Additionally, IL-20RA emerges as a potential common risk factor for three diabetic microvascular complications. These findings may provide novel insights into early prevention and new therapeutic strategies for diabetic microvascular complications.