Background: The impact of inflammatory factors on the risk of diabetic nephropathy (DN) is inconsistent. Two-sample Mendelian randomization (MR) analyses were used to detect the causal role of inflammatory factors in DN risk.
Methods: Inflammatory factor GWAS summary data were collected from a meta-analysis including 8,293 Finnish participants, and DN information was extracted from a GWAS of 213,746 individuals from FinnGen. The MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) outlier test was used for the removal of horizontal pleiotropic outliers. Multivariable MR analysis was also used to adjust for pleiotropy.
Results: IFN-γ [OR_IVW: 1.33; 95% CI: 1.09– 1.63; p=0.005] and SCF [OR_IVW: 1.25, 1.02– 1.52; p = 0.027] were associated with an increased risk of DN. MIP1b [OR_IVW: 0.92; 95% CI: 0.85– 0.98; p = 0.022] and IL-16 [OR_IVW: 0.89, 0.81– 0.99; p = 0.043] showed negative associations with the risk of DN. We validated our MR results with MR-PRESSO analyses. Significant horizontal pleiotropy was not found. Moreover, in the multivariable MR analysis, the associations between cytokines and DN risk remained.
Conclusion: Our MR results based on genetic data contribute to a better understanding of the pathogenesis of DN and provide evidence for a causal effect of inflammatory factors on DN. These findings support targeting specific inflammatory factors to alleviate DN risk.

Keywords: causal association, diabetic nephropathy, inflammatory factors, Mendelian randomization