RESUMEN
Background: Multiple clinical studies have observed a close relationship between serum trace elements and nutrients and diabetes and its complications, but it remains unclear whether there is a genetic causal effect between serum trace elements and nutrients and diabetes and its complications. Objective: This study aims to investigate the causal effects of serum trace elements and nutrients on diabetes and its complications using Mendelian randomization methods. Methods: The single nucleotide polymorphisms of serum trace elements and vitamins, as exposure factors, were sourced from the published UK Biobank database and public databases of genome-wide association studies. The genome-wide association study data of diabetes and its complications, as outcome events, were sourced from the FinnGen Biobank database. Mendelian randomization methods were employed to explore the causal relationships between 9 trace elements and 6 nutrients and diabetes and its complications. The causal relationships were inferred using inverse variance weighting, MR Egger, weighted median, simple model, and weighted model methods. Sensitivity analyses, including heterogeneity tests, horizontal pleiotropy tests, MR-PRESSO tests, and leave-one-out analysis, were conducted to evaluate the robustness of the study results. Finally, trace elements and nutrients with statistical significance in the IVW method and consistent Beta and OR directions in the five methods were selected as exposure factors with causal relationships with diabetes and its complications. This study also used multivariable Mendelian randomization methods to assess the combined effects of multiple exposure factors on the risk of diabetes and its complications. Results: Mendelian randomization analysis revealed that selenium was linked to an elevated risk of T2D.Vitamin B6 was correlated with an increased risk of neurological complications in type 2 diabetes. Magnesium exhibited a negative causal relationship with the risk of T1D.Carotene was linked to a higher risk of renal complications in T1D.Vitamin B12 showed a negative causal relationship with renal complications in T1D.Carotene was connected to a higher risk of neurological complications in T1D.Potassium and vitamin B6 exhibited negative causal relationships with neurological complications in T1D.Vitamin E showed a negative causal relationship with peripheral circulation complications in T2D.Multivariable Mendelian randomization analysis suggested that vitamin B6 could independently influence neurological complications in both T1D and T2D, apart from other exposure factors. Vitamin B6 could also independently influence renal complications in T1D.Vitamin E could independently influence peripheral circulation complications in T1D, apart from other exposure factors. Conclusion: The findings from univariable and multivariable Mendelian randomization studies substantiate the causal relationships between trace elements and nutrients and different subtypes of diabetes and their complications. These findings hold significant clinical implications for developing targeted prevention and treatment strategies for diabetes and its complications.
RESUMEN
Background: 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. Methods: 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. Results: 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. Conclusion: 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.