The causal effect of inflammatory proteins and immune cell populations on diabetic nephropathy: evidence from Mendelian randomization

Diabetic nephropathy (DN) is one of the diabetic microvascular complications with complex pathophysiology, and exploring the landscape of immune dysregulation in DN is valuable for pathogenesis and disease treatment. We crystallized possible inflammatory exposures into 91 circulating inflammatory proteins and 109 blood immune cells; and assessed the causal relationship between inflammation and DN using Mendelian randomization (MR).

Based on publicly available genetic data, we explored causal associations between inflammation and DN risk by two-sample MR analysis. Genome-wide association study (GWAS) summary statistics for 91 circulating inflammatory proteins, 109 immune cells absolute counts, and DN were acquired from the GWAS Catalog. Inverse Variance Weighted (IVW) was the main MR method, while MR-Egger and MR-pleiotropy residuals and outliers (MR-PRESSO) were utilized for sensitivity analysis. Cochrane’s Q was used to test for heterogeneity. The leave-one-out method ensured the stability of the MR results.

This study revealed that higher levels of TNF-related activation-induced cytokine and tumor necrosis factor ligand superfamily member 14 were possibly associated with the increased risk of DN according to the IVW approach, with estimated odds ratios (OR) of 1.287 (95% confidence interval [CI] 1.051 to 1.577, P = 0.015) and 1.249 (95% CI 1.018 to 1.532, P = 0.033). Five immune cell traits were identified that might be linked to increased DN risk, including the higher absolute counts of HLA DR⁺ natural killer cell (OR = 1.248, 95% CI 1.055 to 1.476, P = 0.010), IgD⁺ CD38⁺ B cell (OR = 1.148, 95% CI 1.033 to 1.276, P = 0.010), CD25⁺⁺ CD8⁺ T cell (OR = 1.159, 95% CI 1.032 to 1.302, P = 0.013), CD4⁻ CD8⁻ T cell (OR = 1.226, 95% CI 1.032 to 1.457, P = 0.020), and IgD⁻ CD38⁻ B cell (OR = 1.182, 95% CI 1.009 to 1.386, P = 0.039). In addition, elevated levels of interleukin-1 alpha (OR = 0.712, 95% CI 0.514 to 0.984, P = 0.040) and unswitched memory B cell (OR = 0.797, 95% CI 0.651 to 0.974, P = 0.027) may reduce the risk of developing DN.

We identified inflammation-related exposures that may be associated with the risk of DN at the level of genetic prediction, which contributes to a better understanding of the etiologic of DN and facilitates the development of targeted therapies for DN.