Association of circulating inflammatory proteins with type 2 diabetes mellitus and its complications: a bidirectional Mendelian randomization study.

Abstract

Increasing evidence indicates that immune response underlies the pathology of type 2 diabetes (T2D). Nevertheless, the specific inflammatory regulators involved in this pathogenesis remain unclear. We systematically explored circulating inflammatory proteins that are causally associated with T2D via a bidirectional Mendelian randomization (MR) study and further investigated them in prevalent complications of T2D. Genetic instruments for 91 circulating inflammatory proteins were derived from a genome-wide association study (GWAS) that enrolled 14,824 predominantly European participants. Regarding the summary-level GWASs of type 2 diabetes, we adopted the largest meta-analysis of European population (74,124 cases vs. 824,006 controls) and a prospective nested case-cohort study in Europe (9,978 cases vs. 12,348 controls). Summary statistics for five complications of T2D were acquired from the FinnGen R9 repository. The inverse variance-weighted method was applied as the primary method for causal inference. MR-Egger, weighted median and maximum likelihood methods were employed as supplementary analyses. Results from the two T2D studies were combined in a meta-analysis. Sensitivity analyses and phenotype-wide association studies (PheWAS) were performed to detect heterogeneity and potential horizontal pleiotropy in the study. Genetic evidence indicated that elevated levels of TGF-α (OR = 1.16, 95% CI = 1.15-1.17) and CX3CL1 (OR = 1.30, 95% CI = 1.04-1.63) promoted the occurrence of T2D, and increased concentrations of FGF-21 (OR = 0.87, 95% CI = 0.81-0.93) and hGDNF (OR = 0.96, 95% CI = 0.95-0.98) mitigated the risk of developing T2D, while type 2 diabetes did not exert a significant influence on said proteins. Elevated levels of TGF-α were associated with an increased risk of ketoacidosis, neurological complications, and ocular complications in patients with T2D, and increased concentrations of FGF-21 were potentially correlated with a diminished risk of T2D with neurological complications. Higher levels of hGDNF were associated with an increased risk of T2D with peripheral vascular complications, while CX3CL1 did not demonstrate a significant association with T2D complications. Sensitivity analyses and PheWAS further ensure the robustness of our findings. This study determined four circulating inflammatory proteins that affected the occurrence of T2D, providing opportunities for the early prevention and innovative therapy of type 2 diabetes and its complications.