Abstract
AIMS: IgA nephropathy (IgAN) and membranous nephropathy (MN) have intricate etiologies that are poorly understood. This study aimed to investigate the impact of genetically predicted environmental factors on IgAN and MN. METHODS: We used bidirectional two-step Mendelian randomization (MR) analysis utilizing large-scale genome-wide association study (GWAS) data to investigate the relationships between 68 environmental exposures and IgAN and MN. The main method is inverse variance weighted (IVW). Sensitivity analyses were conducted to validate the causal estimates. Furthermore, the two-step MR was used to explore possible mediating effects. RESULTS: A total of 20 significant causal associations were identified. Genetically predicted educational attainment (EA), average household income, gluten-free diet, cheese intake, fresh fruit intake, cognitive performance, and intelligence were associated with a reduced risk of IgAN (p < 0.05); whereas frequency of alcohol consumption, insomnia, triglycerides, transferrin saturation, percentage body fat, body mass index (BMI), waist circumference, and blood pressure were associated with the risk of IgAN (p < 0.05). Genetically predicted EA and moderate to vigorous physical activity were associated with a reduced risk of MN (p < 0.05); on the other hand, beef intake, waist-to-hip ratio, and nitrogen oxides were associated with the risk of MN (p < 0.05). In addition, we observed that insomnia, BMI, and waist circumference partially mediated the causal link between EA and IgAN, with mediation proportions of 12.52%, 11.06%, and 9.93%, respectively. CONCLUSIONS: This study provides novel evidence of causal relationships between 20 genetically predicted environmental factors and the risk of IgAN and MN. These findings may inform targeted prevention strategies and contribute to improved disease risk assessment.