Etiology of nephrotic syndrome: insights from univariate and multivariate Mendelian randomization study

Nephrotic syndrome (NS) is a common cause of chronic glomerular disease. However, the precise way in which one or more risk exposure traits of renal injury lead to NS remains unclear. In this study, we systematically examined the causal relationships between NS and various exposure traits, including traits related to chronic hepatitis B/C infection, COVID-19 (hospitalized), general allergy status, herbal tea intake, immunoglobulin E, childhood obesity, and the human leukocyte antigen (HLA)-II histocompatibility DM α/DP β1/DQ α2 chain, via multivariate Mendelian randomization (MVMR). A previously reported exposure trait, ulcerative colitis, was also included to analyze the independent effect of each significant exposure on the risk of developing NS. In the univariable MR analysis, immunoglobulin E (OR = 5.62, 95% CI = 2.91-10.84, p = 2.67 × 10^-7) and the HLA-II histocompatibility DQ α2 chain (OR = 0.70, 95% CI = 0.63-0.80, p = 2.83 × 10^-7) were shown to have effect estimates consistent with a greater risk of developing NS. The reverse MR analysis showed no evidence of causal effect from NS to histocompatibility DQ α2 chain (p = 0.76). In MVMR, only the HLA-II histocompatibility DQ α2 chain retained a robust effect (OR = 0.71, 95% CI = 0.61-0.82; p = 9.39 × 10^-6), and the estimate for immunoglobulin E was weakened (OR = 1.04, 95% CI = 0.60-2.13; p = 0.92). With two independent ulcerative colitis resources used for validation, ulcerative colitis was not significantly associated with NS. This study provides genetic evidence that the HLA-II histocompatibility DQ α2 chain has a predominant causal effect on the risk of developing NS. HLA-II histocompatibility-mediated immune abnormalities may lead to subtypes of NS and its pathological changes.