Dissecting causal relationships between immune cells, blood metabolites, and diabetic nephropathy

Clinical observations suggest a strong association between Diabetic nephropathy (DN) and immune cells, though the mediating mechanisms remain unclear. This study aimed to explore the causal effects of immune cells on DN and to clarify how specific blood metabolites mediate this relationship.

Mendelian randomization (MR) analysis was employed to assess the causal link between immune cells and DN and to identify potential blood metabolites as mediators. A total of 731 immune cells and 1400 blood metabolites were examined in relation to DN using a Genome-wide association study (GWAS), with a two-step MR approach utilized for comprehensive analysis. The primary method was the Inverse Variation Weighted (IVW) method, supplemented by MR-Egger, MR-PRESSO and MR-Radial for sensitivity assessments, with Cochrane's Q and I² statistic evaluating heterogeneity.

Two-sample MR revealed significant associations between 17 immune cells and DN(P < 0.05), with reverse MR yielding negative results. Additionally, 25 blood metabolites showed significant associations with DN. Notably, for the two-step Mendelian randomization analysis, we identified 6 significant mediating pathways where 5 blood metabolites served as mediators in the significant link between 6 immune cell groups and DN. Among them, the mediators Carotenoid levels (cryptoxanthin) have a high mediation proportion from EM CD8br %CD8br to DN (beta = -0.0057, 95% CI [-0.0111, -0.0003], P = 0.0397) with a mediation proportion of 9.97% (95% CI:19.50%, 0.47%). Overall, mediation proportions for all these immune-metabolite-DN pathways ranged from 7.22% to 10.3%.

This MR study provides novel genetic evidence of a significant relationship between certain immune cells and DN, with blood metabolites playing a mediating role. These findings offer valuable insights for potential clinical interventions.