Comprehensive Mendelian randomization analysis and experimental investigation identifies the causal relationship...

This study investigated the causal relationship between immunity and kidney stone disease (KSD) by utilizing a Mendelian Randomization (MR) framework. We conducted a proteome-wide analysis to identify proteins associated with kidney stone disease risk using data from 4907 plasma proteins. Additionally, genetic instruments were employed to assess the impact of immune traits, including circulating inflammatory proteins, immune cell traits, immune-mediated diseases, and mRNA expression on kidney stone disease. Immunofluorescence staining was also performed to confirm gene expression patterns in kidney tissues affected by Randall's Plaque (RP). The results of the inverse variable weighting method showed that 174 plasma proteins were positively associated with KSD [ P < 0.05, odds ratio (OR) > 1]; 48 plasma proteins were negatively associated with KSD (P < 0.05, OR < 1). Subsequently, GO and KEGG analysis showed significant enrichment in immune pathways. Notably, elevated levels of inflammatory proteins such as CCL19 (OR per SD, 1.084; 95% CI = 1.006-1.167), OSM (OR per SD, 1.120; 95% CI = 1.023-1.227), and FGF5 (OR per SD, 1.077; 95% CI = 1.020-1.136) were associated with an increased risk of KSD. We also observed positive associations between 20 certain immune cell traits and KSD, while others 11 showed a negative correlation. Additionally, immune-mediated diseases, including psoriasis, Crohn's disease, and rheumatoid arthritis, were found to increase the risk of KSD (P < 0.05, OR > 1). Finally, summary-data-based MR analysis identified HLA-C, C4A and MICA as key immune system genes in blood and kidney eQTL data. Immunofluorescence staining verified the differential expression of HLA - C and C4A in clinical RP tissues.