Exploring the potential causal association between genetic factors for multiple sclerosis and genetic factors for kidney disease: A multivariate Mendelian randomization study

The potential causal relationship between genetic susceptibility to multiple sclerosis (MS) and the risk of kidney diseases remains unclear. Understanding this association may provide new insights into comorbidity mechanisms and improve clinical risk assessment. A two-sample Mendelian randomization (MR) analysis was conducted using single nucleotide polymorphisms significantly associated with MS as instrumental variables. Genetic data were derived from genome-wide association studies comprising 115,803 individuals for MS and up to 218,792 individuals for renal diseases. Outcomes included nephrotic syndrome, glomerulonephritis, tubulointerstitial nephritis, and diabetic nephropathy. Causal estimates were calculated using inverse variance weighted, MR-Egger, weighted median, and simple mode methods. Pleiotropy and heterogeneity were assessed using MR-Egger intercept and Mendelian Randomization Pleiotropy RESidual Sum and Outlier tests. Inverse variance weighted analysis indicated a positive association between genetic liability to MS and nephrotic syndrome (odds ratio = 1.14, 95% confidence interval: 1.03–1.26; P = .009), and a negative association with diabetic nephropathy (odds ratio = 0.83, 95% confidence interval: 0.73–0.95; P = .006). No significant associations were found with glomerulonephritis or tubulointerstitial nephritis. Sensitivity analyses revealed no evidence of directional pleiotropy or influential outliers. Genetic predisposition to MS may increase the risk of nephrotic syndrome while reducing the risk of diabetic nephropathy. These findings suggest shared immunogenetic mechanisms and highlight the importance of renal surveillance in MS management.