Bidirectional Mendelian randomization analysis of the causal associations between serum vitamin D levels and multiple kidney diseases

Abstract

The relationship between vitamin D levels and the risk of kidney diseases, such as IgA nephropathy (IgAN), membranous nephropathy (MN), and diabetic nephropathy (DN), is still debated in observational studies. This research aims to evaluate the causal relationships between vitamin D and these kidney diseases using a bidirectional Mendelian randomization (MR) approach. We obtained summary-level data from genome-wide association studies (GWAS) on serum 25(OH)D levels, IgAN, MN, and DN to assess the causal impact of vitamin D on these kidney diseases. The primary method used for MR analysis was the inverse variance weighted (IVW) approach. To further ascertain the stability and reliability of our results, we performed sensitivity analyses including Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis, which helped identify potential pleiotropy and outlier single nucleotide polymorphisms (SNPs) influencing the associations. Our analysis revealed no causal relationships between serum 25(OH)D levels and the risks of IgAN, MN, and DN. Sensitivity analyses confirmed the robustness of the MR findings. This MR analysis robustly refutes causal associations between genetically determined 25(OH)D levels and IgAN, MN, and DN. These null findings challenge the paradigm of vitamin D supplementation as a preventive strategy for these nephropathies, urging clinicians to prioritize interventions targeting modifiable risk factors over vitamin D optimization in kidney disease management.

Fig. 1

Diagram of Mendelian randomization framework in this study.

Fig. 2

The MR analysis scatter plot for the assessment of the causal relationship between serum 25(OH)D levels and the risk of IgAN, MN and DN. Five methods including inverse variance weighting, MR-Egger, simple mode, weighted median and weighted mode were used in MR analyses. (A) serum 25(OH)D levels show no causal relationship with IgAN incidence (all P > 0.05); (B) IgAN show no causal relationship with serum 25(OH)D levels (all P > 0.05); (C) serum 25(OH)D levels show no causal relationship with MN incidence (all P > 0.05); (D) MN show no causal relationship with serum 25(OH)D levels (all P > 0.05); (E) serum 25(OH)D levels show no causal relationship with DN incidence (all P > 0.05); (F) DN show no causal relationship with serum 25(OH)D levels (all P > 0.05).

Fig. 3

Leave-one-out sensitivity analysis of the causal association between serum 25(OH)D levels and IgAN, MN and DN (Each row represents the IVW-derived causal effect estimate after sequentially excluding the corresponding SNP; “All” indicates the causal effect estimate using all included SNPs). (A) serum 25(OH)D levels on IgAN, after eliminating the outlier rs12501515, the result was robust; (B) IgAN on serum 25(OH)D levels, no outliers were observed; (C) serum 25(OH)D levels on MN, no outliers were observed; (D) MN on serum 25(OH)D levels, no outliers were observed; (E) serum 25(OH)D levels on DN, after eliminating the outlier rs3829251, the result was robust; (F) DN on serum 25(OH)D levels, no outliers were observed.