A phenome-wide association and mendelian randomization study of genetically predicted membranous nephropathy with multiple diseases

Background: Membranous nephropathy constitutes a significant proportion of cases leading to end-stage renal disease. In such instances, the accurate distinction between primary and secondary forms is crucial for proper treatment. Consequently, we systematically examined the link between genetically predicted membranous nephropathy and various diseases. Methods: The phenome-wide association approach assessed the links between genetically predicted membranous nephropathy and 2,408 diseases. Two-sample Mendelian randomization was then employed to explore causal relationships using methods like inverse variance weighting, MR-Egger, weighted median, and others. A replication analysis was conducted to confirm these associations. Gene enrichment analysis was conducted using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses to explore potential pathogenic mechanisms. Results: A statistically significant association was noted between genetically predicted Graves’ disease, thyrotoxicosis, and thyrotoxicosis with diffuse goiter and an elevated risk of membranous nephropathy. Subsequent replication analysis for Graves’ disease demonstrated consistent results. Functional analysis suggests that Graves’ disease may affect membranous nephropathy by influencing pathophysiological mechanisms and pathways related to the proliferation and differentiation of lymphocytes and leukocytes, adhesion between leukocytes, and cells, differentiation of CD4+ αβ T cells, and differentiation of Th1 and Th2 cells. Conclusions: Our study indicates that genetically predicted thyrotoxicosis, thyrotoxicosis with diffuse goiter, and Graves’ disease are correlated with an increased likelihood of membranous nephropathy. Graves’ disease may affect membranous nephropathy development by influencing leukocyte proliferation and differentiation. Additional research is warranted to validate these findings and ascertain their relevance in clinical management.